Diphenylazetidinone derivatives for treating disorders of the lipid metabolism

ABSTRACT

Compounds of formula (I): (wherein variable groups are as defined within) pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia are described. Processes for their manufacture and pharmaceutical compositions containing them are also described

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application PCT/GB2003/002811, filed Jul. 1, 2003, whichclaims priority from United Kingdom Application No. 0215579.4, filedJul. 5, 2002 the specifications of each of which are incorporated byreference herein. International Application PCT/GB2003/002811 waspublished under PCT Article 21(2) in English.

This invention relates to 2-azetidinone derivatives, or pharmaceuticallyacceptable salts, solvates, solvates of such salts and prodrugs thereof.These 2-azetidinones possess cholesterol absorption inhibitory activityand are accordingly of value in the treatment of disease statesassociated with hyperlipidaemic conditions. They are therefore useful inmethods of treatment of a warm-blooded animal, such as man. Theinvention also relates to processes for the manufacture of said2-azetidinone derivatives, to pharmaceutical compositions containingthem and to their use in the manufacture of medicaments to inhibitcholesterol absorption in a warm-blooded animal, such as man. A furtheraspect of this invention relates to the use of the compounds of theinvention in the treatment of dyslipidemic conditions.

Atherosclerotic coronary artery disease is a major cause of death andmorbidity in the western world as well as a significant drain onhealthcare resources. It is well-known that hyperlipidaemic conditionsassociated with elevated concentrations of total cholesterol and lowdensity lipoprotein (LDL) cholesterol are major risk factors forcardiovascular atherosclerotic disease (for instance “Coronary HeartDisease: Reducing the Risk; a Worldwide View” Assman G., Carmena R.Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes andCardiovascular Disease: A Statement for Healthcare Professionals fromthe American Heart Association” Grundy S, Benjamin I., Burke G., et al;Circulation, 1999, 100, 1134-46).

The concentration of plasma cholesterol depends on the integratedbalance of endogenous and exogenous pathways of cholesterol metabolism.In the endogenous pathway, cholesterol is synthesized by the liver andextra hepatic tissues and enters the circulation as lipoproteins or issecreted into bile. In the exogenous pathway cholesterol from dietaryand biliary sources is absorbed in the intestine and enters thecirculation as component of chylomicrons. Alteration of either pathwaywill affect the plasma concentration of cholesterol.

The precise mechanism by which cholesterol is absorbed from theintestine is however not clear. The original hypothesis has been thatcholesterol is crossing the intestine by unspecific diffusion. But morerecent studies are suggesting that there are specific transportersinvolved in the intestinal cholesterol absorption. (See for instance Newmolecular targets for cholesterol-lowering therapy Izzat, N. N.,Deshazer, M. E. and Loose-Mitchell D. S. JPET 293:315-320, 2000.)

A clear association between reduction of total cholesterol and (LDL)cholesterol and decreased instance of coronary artery disease has beenestablished, and several classes of pharmaceutical agents are used tocontrol serum cholesterol. There major options to regulate plasmacholesterol include (i) blocking the synthesis of cholesterol by agentssuch as HMG-CoA reductase inhibitors, for example statins such assimvastatin and fluvastatin, which also by up-regulation ofLDL-receptors will promote the cholesterol removal from the plasma; (ii)blocking the bile acid reabsorption by specific agents resulting inincreased bile acid excretion and synthesis of bile acids fromcholesterol with agents such as bile acid binders, such as resins e.g.cholestyramine and cholestipol; and (iii) by blocking the intestinaluptake of cholesterol by selective cholesterol absorption inhibitors.High density lipoprotein (HDL) elevating agents such as fibrates andnicotinic acid analogues have also been employed.

Even with the current diverse range of therapeutic agents, a significantproportion of the hypercholesterolaemic population is unable to reachtarget cholesterol levels, or drug interactions or drug safety precludethe long term use needed to reach the target levels. Therefore there isstill a need to develop additional agents that are more efficacious andare better tolerated.

Compounds possessing such cholesterol absorption inhibitory activityhave been described, see for instance the compounds described in WO93/02048, WO 94/17038, WO 95/08532, WO 95/26334, WO 95/35277, WO96/16037, WO 96/19450, WO 97/16455, WO 02/50027, WO 02/50060, WO02/50068, WO 02/50090, WO 02/66464, U.S. Pat. No. 5,756,470, U.S. Pat.No. 5,767,115 and US RE37721.

The present invention is based on the discovery that certainbenzothiazepine and benzothiadiazepine compounds surprisingly inhibitcholesterol absorption. Such properties are expected to be of value inthe treatment of disease states associated with hyperlipidaemicconditions. The compounds of the present invention are not disclosed inany of the above applications and we have surprisingly found that thesecompound possess beneficial efficacious, metabolic and toxicologicalprofiles that make them particularly suitable for in vivo administrationto a warm blooded animal, such as man. In particular certain compoundsof the present invention have a low degree of absorption compared to thecompounds of the prior art whilst retaining their ability to inhibitcholesterol absorption.

Accordingly there is provided a compound of formula (I):

wherein:

Ring A is selected from phenyl or thienyl;

X is selected from —CR²R³—, —O—, —NR^(x)— and —S(O)_(a)—; wherein R^(x)is hydrogen or C₁₋₆alkyl, and a is 0-2;

Y is selected from —CR⁴R⁵—, —O—, —NR^(z)— and —S(O)_(a)—; wherein R^(z)is hydrogen or C₁₋₆alkyl, and a is 0-2; wherein there is at least one—CR²R³— or —CR⁴R⁵— group;

R¹ is independently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxyand C₁₋₆-alkylS(O)_(a) wherein a is 0 to 2; wherein R¹ is independentlyoptionally substituted on carbon by one or more halo, C₁₋₆alkoxy andhydroxy;

b is 0-3; wherein the values of R¹ may be the same or different;

R² and R³ are independently selected from hydrogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy and C₁₋₆alkanoyloxy; wherein R² and R³ may be independentlyoptionally substituted on carbon by one or more halo or hydroxy; or R²and R³ together form an oxo group;

R⁴ and R⁵ are independently selected from hydrogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy and C₁₋₆alkanoyloxy; or R⁴ and R⁵ together form an oxo group;

R⁶ is independently selected from halo, nitro, cyano, hydroxy, amino,carboxy, formyl, carbamoyl, carbamoyloxy, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkenyloxy, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,C₁₋₆-alkanoyl-N-(C₁₋₆alkyl)amino, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, N-(C₁₋₆alkyl)carbamoyloxy,N,N-(C₁₋₆alkyl)₂carbamoyloxy, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,C₁₋₆alkoxycarbonyl-N-(C₁₋₆alkyl)amino, C₁₋₆alkoxycarbonyloxy,C₁₋₆alkoxycarbonylamino, ureido, N′-(C₁₋₆alkyl)ureido,N-(C₁₋₆alkyl)ureido, N′,N′-(C₁₋₆alkyl)₂ureido,N′-(C₁₋₆alkyl)-N-(C₁₋₆alkyl)ureido,N′,N′-(C₁₋₆alkyl)₂-N-(C₁₋₆alkyl)ureido, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl and phenyl; wherein R⁷ is independentlyoptionally substituted on carbon by one or more halo, C₁₋₆alkoxy,hydroxy, amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkanoylamino,C₁₋₆alkanoyl-N-(C₁₋₆alkyl)amino, phenyl, phenoxy, benzoyl,phenylC₁₋₆alkyl and phenylC₁₋₆alkoxy;

c is 0-5; wherein the values of R⁶ may be the same or different;

R⁷ is independently selected from halo, hydroxy, cyano, carbamoyl,ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido,acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,N-methylsulphamoyl and N,N-dimethylsulphamoyl;

d is 0-4; wherein the values of R⁷ may be the same or different;

R⁹ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁹ maybe optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴;

R¹⁰ is hydrogen or C₁₋₄alkyl;

R¹¹ and R¹² are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; or R¹¹ and R¹² together form C₂₋₆alkylene;wherein R¹¹ and R¹² or R¹¹ and R¹² together may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R²⁶;

R¹³ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹³ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁷; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R²⁸;

R¹⁴ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R²⁹—(C₁₋₁₀alkylene)_(f)-,heterocyclyl-(C₁₋₁₀alkylene)_(g)-R³⁰—(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, phosphono, —P(O)(OR³¹)(OR³²), —P(O)(OH)(OR³¹),—P(O)(OH)(R³¹) or —P(O)(OR³¹)(R³²) wherein R³¹ and R³² are independentlyselected from C₁₋₆alkyl; wherein R¹⁴ may be optionally substituted oncarbon by one or more substituents selected from R³³; and wherein ifsaid heterocyclyl contains an —NH— group, that nitrogen may beoptionally substituted by a group selected from R³⁴; or R¹⁴ is a groupof formula (IA):

wherein:

Z is —N(R³⁵)—, —N(R³⁵)C(O)—, —O—, and —S(O)_(a)—; wherein a is 0-2 andR³⁵ is hydrogen or C₁₋₄alkyl;

R¹⁵ is hydrogen or C₁₋₄alkyl;

R¹⁶ and R¹⁷ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, sulpho, sulphino, amidino, phosphono, —P(O)(OR³⁶)(OR³⁷),—P(O)(OH)(OR³⁶), —P(O)(OH)(R³⁶) or —P(O)(OR³⁶)(R³⁷), wherein R³⁶ and R³⁷are independently selected from C₁₋₆alkyl; wherein R¹⁶ and R¹⁷ may beindependently optionally substituted on carbon by one or moresubstituents selected from R³⁸; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R³⁹;

R¹⁸ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl, C₁₋₁₀alkoxycarbonyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl, carbocyclylC₁₋₁₀alkyl, heterocyclyl,heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁴⁰—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁴¹—(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, phosphono, —P(O)(OR⁴²)(OR⁴³), —P(O)(OH)(OR⁴²),—P(O)(OH)R⁴²) or —P(O)(OR⁴²)(R⁴³) wherein R⁴² and R⁴³ are independentlyselected from C₁₋₆alkyl; wherein R¹⁸ may be optionally substituted oncarbon by one or more substituents selected from R⁴⁴; and wherein ifsaid heterocyclyl contains an —NH— group, that nitrogen may beoptionally substituted by a group selected from R⁴⁵; or R¹⁸ is a groupof formula (IB):

wherein:

R¹⁹ is selected from hydrogen or C₁₋₄alkyl;

R²⁰ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR⁴⁶)(OR⁴⁷), —P(O)(OH)(OR⁴⁶), —P(O)(OH)(R⁴⁶)or —P(O)(OR⁴⁶)(R⁴⁷), wherein R⁴⁶ and R⁴⁷ are independently selected fromC₁₋₆alkyl; where R²⁰ may be independently optionally substituted oncarbon by one or more substituents selected from R⁴⁸; and wherein ifsaid heterocyclyl contains an —NH— group, that nitrogen may beoptionally substituted by a group selected from R⁴⁹;

R² is selected from halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁵⁰—(C₁₋₁₀alkylene)_(f)-,heterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁵¹-(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, phosphono, —P(O)(OR⁵²)(OR⁵³), —P(O)(OH)(OR⁵²),—P(O)(OH)(R⁵²) or —P(O)(OR⁵³)(R⁵³) wherein R⁵² and R⁵³ are independentlyselected from C₁₋₆alkyl; wherein R²¹ may be independently optionallysubstituted on carbon by one or more R⁵⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R⁵⁵;

p is 1-3; wherein the values of R⁶ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁷ may be the same or different;

m is 0-2; wherein the values of R¹³may be the same or different;

n is 1-2;wherein the values of R⁹ may be the same or different;

z is 0-3; wherein the values of R²⁰ may be the same or different;

R²³, R²⁵, R²⁷, R³³, R³⁸, R⁴⁴, R⁴⁸ and R⁵⁴ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,C₁₋₁₀alkoxycarbonyl, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁵⁶—(C₁₋₁₀alkylene)_(f)-,heterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁵⁷-(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, amidino, phosphono, —P(O)(OR⁵⁸)(OR⁵⁹),—P(O)(OH)(OR⁵⁸), —-P(O)(OH)(R⁵⁸) or —P(O)(OR⁵⁹)(R⁵⁹), wherein R⁵⁸ andR⁵⁹ are independently selected from C₁₋₆alkyl; wherein R²³, R²⁵, R²⁷,R³³, R³⁸, R⁴⁴, R⁴⁸ and R⁵⁴ may be independently optionally substitutedon carbon by one or more R⁶⁰; and wherein if said heterocyclyl containsan —NH— group, that nitrogen may be optionally substituted by a groupselected from R⁶¹;

R²⁴, R²⁶, R²⁸, R³⁴, R³⁹, R⁴⁵, R⁴⁹, R⁵⁵ and R⁶¹ are independentlyselected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, sulphamoyl,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkoxycarbonyl,carbamoyl, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, benzyl,phenethyl, benzoyl, phenylsulphonyl and phenyl;

R²⁹, R³⁰, R⁴⁰, R⁴¹, R⁵⁰, R⁵¹, R⁵⁶ and R⁵⁷are independently selected from—O—, —NR⁶²—, —S(O)_(x)—, —NR⁶²C(O)NR⁶³—, —NR⁶²C(S)NR⁶³—, —OC(O)N═C—,—NR⁶²C(O)— or —C(O)NR⁶²—; wherein R⁶² and R⁶³ are independently selectedfrom hydrogen or C₁₋₆alkyl, and x is 0-2;

R⁶⁰ is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino,nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy,methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl andN,N-dimethylsulphamoyl; and

e, f, g and h are independently selected from 0-2;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₁₀alkyl”, “C₁₋₆alkyl” and “C₁₋₄alkyl” include propyl,isopropyl and t-butyl. However, references to individual alkyl groupssuch as ‘propyl’ are specific for the straight chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched chain version only. A similar conventionapplies to other radicals, for example “phenylC₁₋₆alkyl” would includebenzyl, 1-phenylethyl and 2-phenylethyl. The term “halo” refers tofluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 3-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)— or a ring sulphur atom may beoptionally oxidised to form the S-oxides. Particularly a “heterocyclyl”is a saturated, partially saturated or unsaturated, mono or bicyclicring containing 5 or 6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen, which may, unless otherwise specified, becarbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)— or a ring sulphur atom may be optionally oxidisedto form S-oxide(s). Examples and suitable values of the term“heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl,1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,4thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl,1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino,1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl,homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl,indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Particularly “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.More particularly “carbocyclyl” is cyclopropyl, cyclobutyl,1-oxoyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,phenyl or 1-oxoindanyl.

An example of “C₁₋₁₀alkanoyloxy” and “C₁₋₆alkanoyloxy” is acetoxy.Examples of “C₁₋₁₀alkoxycarbonyl” and “C₁₋₆alkoxycarbonyl” includemethoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁₋₁₀alkoxy” and “C₁₋₆alkoxy” include methoxy, ethoxy and propoxy.Examples of “C₁₋₁₀alkanoylamino” and “C₁₋₆alkanoylamino” includeformamido, acetamido and propionylamino. Examples of“C₁₋₆alkanoyl-N—(C₁₋₆alkyl)amino” include acetyl-N-methylamino andpropionyl-N-ethyl-amino. Examples of “C₁₋₁₀alkylS(O)_(a) wherein a is 0to 2” and “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2” include methylthio,ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.Examples of “C₁₋₁₀alkanoyl” and “C₁₋₆alkanoyl” include C₁₋₃alkanoyl,propionyl and acetyl. Examples of “N-(C₁₋₁₀alkyl)amino” and“N-(C₁₋₆alkyl)amino” include methylamino and ethylamino. Examples of“N,N-(C₁₋₁₀alkyl)₂amino” and “N,N-(C₁₋₆alkyl)₂amino” includedi-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examplesof “C₂₋₁₀alkenyl” and “C₂₋₆alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₁₀alkynyl” and “C₂₋₆alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “C²⁻⁶alkylene” are ethylene, propylene andbutylene. Examples of “C₂₋₆alkenyloxy” are vinyloxy, allyloxy and1-propenyloxy. Examples of “N-(C₁₋₁₀alkyl)sulphamoyl” and“N-(C₁₋₆alkyl)sulphamoyl” are N-(C₁₋₃alkyl)sulphamoyl,N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N-(C₁₋₁₀alkyl)₂sulphamoyl” and “N-(C₁₋₆alkyl)₂sulphamoyl” areN,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of“N-(C₁₋₁₀alkyl)carbamoyl” and “N-(C₁₋₆alkyl)carbamoyl” aremethylaminocarbonyl and ethylaminocarbonyl. Examples of“N,N-(C₁₋₁₀alkyl)₂carbamoyl” and “N,N-(C₁₋₆alkyl)₂carbamoyl” aredimethylaminocarbonyl and methylethylaminocarbonyl. Examples of“N-(C₁₋₁₀alkyl)carbamoyl” and “N-(C₁₋₆alkyl)carbamoyloxy” aremethylaminocarbonyloxy and ethylaminocarbonyloxy. Examples of“N,N-(C₁₋₁₀alkyl)₂carbamoyl” and “N,N-(C₁₋₆alkyl)₂carbamoyloxy” aredimethylaminocarbonyloxy and methylethylaminocarbonyloxy. Examples of“C₁₋₆alkylsulphonyl” are mesyl and ethylsulphonyl. Examples of“C₁₋₁₀alkylsulphonylamino” and “C₁₋₆alkylsulphonylamino” are mesylaminoand ethylsulphonylamino. Examples of“C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino” are mesyl-N-methylamino andethylsulphonyl-N-propylamino. Examples of “N′-(C₁₋₆alkyl)ureido” areN′-methylureido and N′-i-propylureido. Examples of “N-(C₁₋₆alkyl)ureido”are N-methylureido and N-i-propylureido. Examples of“N′,N′-(C₁₋₆alkyl)₂ureido” are N′,N′-dimethylureido andN′-methyl-N′-ethylureido. Examples of“N′-(C₁₋₆alkyl)-N-(C₁₋₆alkyl)ureido” are N′,N-dimethylureido andN′-methyl-N-ethylureido. Examples of“N′,N′-(C₁₋₆alkyl)₂-N-(C₁₋₆alkyl)ureido” areN′,N′-dimethyl-N-methylureido and N′-methyl-N′-ethyl-N-t-butylureido.Examples of “N,N,N-(C₁₋₁₀alkyl)₃ammonio” are trimethylamino andmethyldiethylamino. Examples of “C₁₋₁₀alkoxycarbonylamino” and“C₁₋₆alkoxycarbonylamino” are methoxycarbonylamino andt-butoxycarbonylamino. Examples of “N-(C₁₋₁₀alkyl)sulphamoylamino” areN-methylsulphamoylamino and N-ethylsulphamoylamino. Examples of“N,N-(C₁₋₁₀alkyl)₂sulphamoylamino” are N,N-dimethylsulphamoylamino andN-methyl-N-ethylsulphamoylamino. Examples of “carbocyclylC₁₋₁₀alkyl”include benzyl and phenethyl. Examples of “heterocyclylC₁₋₁₀alkyl”include 2-morphoinopropyl and pyridylmethyl. Examples of“phenylC₁₋₆alkoxy” include 2-phenylethoxy and 2-phenylpropoxy.

A suitable pharmaceutically acceptable salt of a compound of theinvention, or other compounds disclosed herein, is, for example, anacid-addition salt of a compound of the invention which is sufficientlybasic, for example, an acid-addition salt with, for example, aninorganic or organic acid, for example hydrochloric, hydrobromic,sulphuric, phosphoric, trifluoroacetic, citric, acetate or maleic acid.In addition a suitable pharmaceutically acceptable salt of a compound ofthe invention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compounds of the formula (I), or other compounds disclosed herein,may be administered in the form of a pro-drug which is broken down inthe human or animal body to give a compound of the formula (I). Examplesof pro-drugs include in vivo hydrolysable esters and in vivohydrolysable amides of a compound of the formula (I).

An in vivo hydrolysable ester of a compound of the formula (I), or othercompounds disclosed herein, containing carboxy or hydroxy group is, forexample, a pharmaceutically acceptable ester which is hydrolysed in thehuman or animal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include C₁₋₆alkoxymethylesters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters forexample pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I), or othercompounds disclosed herein, containing a hydroxy group includesinorganic esters such as phosphate esters and α-acyloxyalkyl ethers andrelated compounds which as a result of the in viva hydrolysis of theester breakdown to give the parent hydroxy group. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of theformula (I), or other compounds disclosed herein, containing a carboxygroup is, for example, a N-C₁₋₆alkyl or N,N-di-C₁₋₆alkyl amide such asN-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl orN,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess cholesterolabsorption inhibitory activity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess cholesterol absorption inhibitoryactivity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess cholesterol absorption inhibitoryactivity.

Particular values are as follows. Such values may be used whereappropriate with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

Ring A is selected from thienyl.

Ring A is selected from phenyl.

X is —CR²R³—.

X is —O—.

X is —NR^(x)—; wherein R^(x) is hydrogen or C₁₋₆alkyl.

X is —S(O)_(a)—; wherein a is 0-2.

X is —CR²R³— wherein one of R² and R³ is hydrogen and the other ishydroxy.

X is —CH₂—.

X is —CH(OH)—.

X is —C(O)—.

X is —S—.

X is —S(O)—.

X is —S(O)₂—.

X is selected from —CR²R³—, —O— and —S(O)_(a)—; wherein a is 0-2.

X is selected from —CR²R³—, —O— and —S(O)_(a)—; wherein a is 0-2; and R²and R³ are independently selected from hydrogen and hydroxy; or R² andR³ together form an oxo group.

X is selected from —CH₂—, —CH(OH)—, —C(O)—, —O——S—, —S(O)— and —S(O)₂—.

Y is —CR⁴R⁵—.

Y is —O—.

Y is —NR^(z)—; wherein R^(z) is hydrogen or C₁₋₆alkyl.

Y is —S(O)_(a)—; wherein a is 0-2.

Y is —CR⁴R⁵— wherein R⁴ and R⁵ are both hydrogen.

Y is —CH₂—.

Y is —S—.

Y is —S(O)—.

Y is selected from —CR⁴R⁵— and —S(O)_(a)—; a is 0 or 1.

Y is selected from —CR⁴R⁵— and —S(O)_(a)—; a is 0 or 1; wherein R⁴ andR⁵ are both hydrogen.

Y is —CH₂—, —S— or —S(O)—.

X is —CR²R³— and Y is —CR⁴R⁵— wherein one of R² and R³ is hydrogen andthe other is hydroxy; and wherein R⁴ and R⁵ are both hydrogen.

X is —CH₂— and Y is —S—.

X is —C(O)— and Y is —S—.

X is —CH₂— and Y is —S(O)—.

X is —C(O)— and Y is —S(O)—.

X is —CH₂— and Y is —S(O)₂—.

X is —C(O)— and Y is —S(O)₂—.

X is —O— and Y is —CH₂—.

X is —CHOH— and Y is —S(O)_(a)—; wherein a is 0-2.

X is —CHOH— and Y is —S—.

X is —CHOH— and Y is —S(O)—.

X is —CHOH— and Y is —S(O)₂—.

R¹ is halo.

R¹ is fluoro.

R¹ is 4 fluoro if Ring A is phenyl.

b is 0-2; wherein the values of R¹ may be the same or different.

b is 0-1.

b is 1.

b is 0.

b is 1; wherein the substituent is para to the X group if Ring A isphenyl.

R² and R³ are independently selected from hydrogen and hydroxy; or R²and R³ together form an oxo group.

R² and R³ are independently selected from hydrogen and hydroxy.

One of R² and R³ is hydrogen and the other is hydroxy.

R⁴ and R⁵ are both hydrogen.

R⁶ is halo or C₁₋₆alkoxy.

R⁶ is halo.

R⁶ is fluoro or methoxy.

R⁶ is fluoro.

R⁶ is 4-fluoro or 4-methoxy.

R⁶ is 4-fluoro.

c is 0-2; wherein the values of R⁶ may be the same or different.

c is 0-1.

c is 1.

c is 0.

c is 1; wherein the substituent is para to the nitrogen of theazetidin-2-one ring.

R⁷ is halo, methoxy or ethoxy.

R⁷ is fluoro or methoxy.

d is 0-2; wherein the values of R⁷ may be the same or different.

d is 0-1.

d is 0.

R⁹ is hydrogen.

R¹⁰ is hydrogen.

R¹¹ and R¹² are independently selected from hydrogen or carbocyclyl.

R¹¹ and R¹² are independently selected from hydrogen or phenyl.

One of R¹¹ and R¹² is hydrogen and the other is phenyl or both R¹¹ andR¹² are hydrogen.

R¹¹ and R¹² are independently selected from hydrogen, C₁₋₄alkyl orcarbocyclyl; wherein R¹¹ and R¹² may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵.

R¹¹ and R¹² are independently selected from hydrogen, methyl, ethyl,butyl, isobutyl or phenyl; wherein R¹¹ and R¹² may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵.

R¹¹ and R¹² are independently selected from hydrogen, C₁₋₄alkyl orcarbocyclyl; wherein R¹¹ and R¹² may be independently optionallysubstituted on carbon by one or more substituents selected from R²⁵;wherein R²⁵ is selected from hydroxy, amino, carbamoyl,C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylamino, carbocyclyl or carboxy;wherein R²⁵ may be optionally substituted on carbon by one or more R⁶⁰;wherein R⁶⁰ is hydroxy.

R¹¹ and R¹² are independently selected from hydrogen, methyl, ethyl,butyl, isobutyl or phenyl; wherein R¹¹ and R¹² may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; wherein R²⁵ is selected from hydroxy, amino, carbamoyl,ethoxycarbonyl, t-butoxycarbonylamino, phenyl or carboxy; wherein R²⁵may be optionally substituted on carbon by one or more R⁶⁰; wherein R⁶⁰is hydroxy.

R¹¹ and R¹² are independently selected from hydrogen, methyl,hydroxymethyl, 2-carbamoylethyl, 2-(ethoxycarbonyl)ethyl,2-carboxyethyl, 4-(t-butoxycarbonylamino)butyl, 4-aminobutyl, isobutyl,phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl.

One of R¹¹ and R¹² is hydrogen and the other is selected from hydrogen,methyl, hydroxymethyl, 2-carbamoylethyl, 2-(ethoxycarbonyl)ethyl,2-carboxyethyl, 4-(t-butoxycarbonylamino)butyl, 4-aminobutyl, isobutyl,phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl.

R¹³ is hydrogen.

R¹⁴ is C₁₋₁₀alkyl, C₁₋₁₀alkoxycarbonyl or carboxy; wherein R¹⁴ may beoptionally substituted on carbon by one or more substituents selectedfrom R³³; or R¹⁴ is a group of formula (IA) as depicted above.

R¹⁴ is C₁₋₆alkyl, C₁₋₆alkoxycarbonyl or carboxy; wherein R¹⁴ may beoptionally substituted on carbon by one or more hydroxy; or R¹⁴ is agroup of formula (IA) as depicted above.

R¹⁴ is 1,2,3,4,5-pentahydroxypentyl, t-butoxycarbonyl or carboxy; or R¹⁴is a group of formula (IA) as depicted above.

R¹⁴ is hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, carboxy orsulpho;

wherein R¹⁴ may be optionally substituted on carbon by one or moresubstituents selected from R³³; or R¹⁴ is a group of formula (IA) (asdepicted above).

R¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl,carboxy or sulpho; wherein R¹⁴ may be optionally substituted on carbonby one or more substituents selected from R³³; or R¹⁴ is a group offormula (IA) (as depicted above).

R¹⁵ is hydrogen.

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy orC₁₋₆alkoxycarbonyl.

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy ort-butoxycarbonyl.

One of R¹⁶ and R¹⁷ is hydrogen, and the other is hydrogen, carboxy ort-butoxycarbonyl.

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy, C₁₋₆alkyland C₁₋₆alkoxycarbonyl.

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy, C₁₋₆alkyland t-butoxycarbonyl.

R¹⁸ is selected from hydroxy, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl orcarboxy.

R¹⁸ is selected from hydroxy, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl or carboxy.

R¹⁸ is selected from hydroxy, t-butoxy, t-butoxycarbonyl or carboxy.

R¹⁸ is selected from hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonyl, carboxy and sulpho.

R¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl,t-butoxycarbonyl, carboxy and sulpho.

p is 1.

q is 0.

r is 0 or 1.

m is 0.

m is 1.

m is 0 or 1.

n is 1.

R¹⁴ is hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, carboxy orsulpho; wherein R¹⁴ may be optionally substituted on carbon by one ormore substituents selected from R³³; or R¹⁴ is a group of formula (IA)(as depicted above) wherein:

R¹⁵ is hydrogen;

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy, C₁₋₆alkyland C₁₋₆alkoxycarbonyl;

R¹⁸ is selected from hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonyl, carboxy and sulpho;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1; and

R³³ is hydroxy.

R¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl,carboxy or sulpho; wherein R¹⁴ may be optionally substituted on carbonby one or more substituents elected from R³³; or R¹⁴ is a group offormula (IA) (as depicted above) wherein:

R¹⁵ is hydrogen;

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy, C₁₋₆alkyland t-butoxycarbonyl;

R¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl,t-butoxycarbonyl, carboxy and sulpho;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1; and

R³³ is hydroxy.

R²⁵ is selected from hydroxy, amino, carbamoyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylamino, carbocyclyl or carboxy; wherein R²⁵ may beoptionally substituted n carbon by one or more R⁶⁰.

R²⁵ is selected from hydroxy, amino, carbamoyl, ethoxycarbonyl,t-butoxycarbonylamino, phenyl or carboxy; wherein R²⁵ may be optionallysubstituted on carbon by one or more R⁶⁰.

R²⁵ is selected from hydroxy, amino, carbamoyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylamino, carbocyclyl or carboxy; wherein R²⁵ may beoptionally substituted on carbon by one or more R⁶⁰; wherein R⁶⁰ ishydroxy.

R²⁵ is selected from hydroxy, amino, carbamoyl, ethoxycarbonyl,t-butoxycarbonylamino, phenyl or carboxy; wherein R²⁵ may be optionallysubstituted on carbon by one or more R⁶⁰; wherein R⁶⁰ is hydroxy.

R³³ is hydroxy.

R⁶⁰ is hydroxy.

The side chain R₁₄—[C(R¹³)]_(m)—C(R¹¹)(R¹²)—N(R¹⁰)—C(O)—[C(R⁹)]_(n)—O—is

N-(2-sulphoethyl)carbamoylmethoxy; N-(carboxymethyl)carbamoylmethoxy;

N-(2-hydroxyethyl)carbamoylmethoxy; N-(2-methoxyethyl)carbamoylmethoxy;

N-[2-(carboxy)ethyl]carbamoylmethoxy;N-[(S)-1-(carboxy)ethyl]carbamoylmethoxy;

N-[(R)-1-(carboxy)ethyl]carbamoylmethoxy; N-[(S)-α-(carboxy)benzyl]carbamoylmethoxy;

N-[(R)-α-(carboxy)benzyl]carbamoylmethoxy;

N-(t-butoxycarbonylmethyl)carbamoylmethoxy;

N-[2-(t-butoxycarbonyl)ethyl]carbamoylmethoxy;

N-[(S)-1,3-bis-(carboxy)propyl]carbamoylmethoxy;

N-((R)-1-carboxy-3-methylbutyl)carbamoylmethoxy;

N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoylmethoxy;

N-[(R)-1-(t-butoxycarbonyl)ethyl]carbamoylmethoxy;

N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoylmethoxy;

N-[(S)-1-(carboxy)-5-(amino)pentyl]carbamoylmethoxy;

N-[(R)-1-(carboxy)-2-(hydroxy)ethyl]carbamoylmethoxy;

N-[(S)-1,3-bis-(ethoxycarbonyl)propyl]carbamoylmethoxy;

N-[(R)-α-(carboxy)-4-(hydroxy)benzyl]carbamoylmethoxy;

N-[N-(carboxymethyl)carbamoylmethyl]carbamoylmethoxy;

N-[(S)-1-(carboxy)-3-(carbamoyl)propyl]carbamoylmethoxy;

N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy;

N-[N-(methoxycarbonylmethyl)carbamoylmethyl]carbamoylmethoxy;

N-((S)-1-{N-[(S)-1-(carboxy)ethyl]carbamoyl}ethyl)carbamoylmethoxy;

N-((2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoylmethoxy;

N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy;

N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy;

N-{N-[(R)-1-(carboxy)-2-(hydroxy)ethyl]carbaoylrethyl}carbamoylmethoxy;

N-[(S)-1-(t-butoxycarbonyl)-5-(t-butoxycarbonylamino)pentyl]carbamoylmethoxy;

N-((S)-1-{N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoyl}ethyl)carbamoylmethoxy;

N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy;

N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy;

N-{N-[(R)-1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoylmethyl}carbamoylmethoxy;or

N-((R)-α-{N-(S)-[1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

Ring A is phenyl;

X is —CR²R³—;

Y is —CR⁴R⁵—;

R¹ is halo;

b is 1;

One of R² and R³ is hydrogen and the other is hydroxy;

R⁴ and R⁵ are both hydrogen;

R⁶ is halo;

c is 1;

d is 0;

R⁹ is hydrogen;

R¹⁰ is hydrogen;

R¹¹ and R¹² are independently selected from hydrogen or carbocyclyl;

R¹⁴ is C₁₋₁₀alkyl, C₁₋₁₀alkoxycarbonyl or carboxy; wherein R¹⁴ may beoptionally substituted on carbon by one or more substituents selectedfrom R³³; or R¹⁴ is a group of formula (IA) as depicted above;

R¹⁵ is hydrogen;

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy orC₁₋₆alkoxycarbonyl;

R¹⁸ is selected from hydroxy, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl orcarboxy;

p is 1;

q is 0;

r is 0 or 1;

m is 0;

n is 1;

R³³ is hydroxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

Ring A is selected from phenyl;

X is —CR²R³— and Y is —CR⁴R⁵— wherein one of R² and R³ is hydrogen andthe other is hydroxy; and wherein R⁴ and R⁵ are both hydrogen;

R¹ is 4-fluoro;

b is 1;

R⁶ is 4-fluoro;

c is 1;

d is 0;

R⁹ is hydrogen;

R¹⁰ is hydrogen;

One of R¹¹ land R¹² is hydrogen and the other is phenyl or both R¹¹ landR¹² are hydrogen;

R¹⁴ is 1,2,3,4,5-pentahydroxypentyl, t-butoxycarbonyl or carboxy; or R¹⁴is a group of formula (IA) as depicted above;

R¹⁵ is hydrogen;

One of R¹⁶ and R¹⁷ is hydrogen, and the other is hydrogen, carboxy ort-butoxycarbonyl;

R¹⁸ is selected from hydroxy, t-butoxy, t-butoxycarbonyl or carboxy;

p is 1;

q is 0;

r is 0 or 1;

m is 0;

n is 1;

R³³ is hydroxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

Ring A is selected from phenyl or thienyl;

X is selected from —CR²R³—, —O— and —S(O)_(a)—; wherein a is 0-2; and R²and R³ are independently selected from hydrogen and hydroxy; or R² andR³ together form an oxo group;

Y is selected from —CR⁴R⁵— and —S(O)_(a)—; a is 0 or 1; wherein R⁴ andR⁵ are both hydrogen;

R¹ is halo;

b is 0-1;

R⁶ is halo;

c is 0-1;

d is 0;

R⁹ is hydrogen;

R¹⁰ is hydrogen;

R¹¹ and R¹² are independently selected from hydrogen, C₁₋₄alkyl orcarbocyclyl;

wherein R¹¹ and R¹² may be independently optionally substituted oncarbon by one or more substituents selected from R²⁵; wherein R²⁵ isselected from hydroxy, amino, carbamoyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylamino, carbocyclyl or carboxy; wherein R²⁵ may beoptionally substituted on carbon by one or more R⁶⁰; wherein R⁶⁰ ishydroxy;

R¹³ is hydrogen;

R¹⁴ is hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, carboxy orsulpho; wherein R¹⁴ may be optionally substituted on carbon by one ormore substituents selected from R³³; or R¹⁴ is a group of formula (IA)(as depicted above) wherein:

R¹⁵ is hydrogen;

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy, C₁₋₆alkyland C₁₋₆alkoxycarbonyl;

R¹⁸ is selected from hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonyl, carboxy and sulpho;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1; and

R³³ is hydroxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

Ring A is selected from phenyl or thienyl;

X is selected from —CH₂—, —CH(OH)—, —C(O)—, —O——S—, —S(O)— and —S(O)₂—;

Y is —CH₂—, —S— or —S(O)—;

R¹ is fluoro;

b is 0-1;

R⁶ is fluoro;

c is 0-1;

d is 0;

R⁹ is hydrogen;

R¹⁰ is hydrogen;

One of R¹¹ and R¹² is hydrogen and the other is selected from hydrogen,methyl, hydroxymethyl, 2-carbamoylethyl, 2-(ethoxycarbonyl)ethyl,2-carboxyethyl, 4-(t-butoxycarbonylamino)butyl, 4-aminobutyl, isobutyl,phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl;

R¹³ is hydrogen;

R¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl,carboxy or sulpho; wherein R¹⁴ may be optionally substituted on carbonby one or more substituents selected from R³³; or R¹⁴ is a group offormula (IA) (as depicted above) wherein:

R¹⁵ is hydrogen;

R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy, C₁₋₆alkyland t-butoxycarbonyl;

R¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl,t-butoxycarbonyl, carboxy and sulpho;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1; and

R³³ is hydroxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the examples or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare:

1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;

1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(R)-α-(carboxy)benzyl]carbamoylmethoxy}phenyl)azetidin-2-one;

1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;

1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[N-(carboxymethyl)carbamoylmethyl]carbamoylmethoxy}phenyl)azetidin-2-one;

1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-hydroxyethyl)carbamoylmethoxy]phenyl}azetidin-2-one;

1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-methoxyethyl)carbamoylmethoxy]phenyl}azetidin-2-one;

3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;

3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;

3-(R)-4-(R)-1-(phenyl)-3-[2-(thien-3-yl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;

3-(R)-4-(R)-1-(phenyl)-3-[2-(thien-3-yl)-2-hydroxyethylsulphanyl]-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;

3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4-[N-(R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;and

3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Preferred aspects of the invention are those which relate to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof which process(wherein variable groups are, unless otherwise specified, as defined informula (I)) comprises of:

Process 1) reacting a compound of formula (II):

with a compound of formula (III):

wherein L is a displaceable group;Process 2) reacting an acid of formula MV):

or an activated derivative thereof; with an amine of formula (V):

Process 3): for compounds of formula (I) wherein R¹⁴ is a group offormula (IA); reacting a compound of formula (VI) wherein R¹⁴ iscarboxy, or an activated derivative thereof, with an amine of formula(VI):

Process 4): for compounds of formula (I) wherein R¹⁴ is a group offormula (IA), Z is —N(R³⁵)C(O)— and q is 1; reacting an acid of formula(VII):

or an activated derivative thereof; with an amine of formula (VIII):

Process 5): for compounds of formula (I) wherein R¹⁴ is a group offormula (IA) and R¹⁸ is a group of formula (IB); reacting an acid offormula (I) wherein R¹⁴ is a group of formula (IA) and R¹⁸ is carboxy,or an activated derivative thereof, with an amine of formula (IX)

Process 6): reacting a compound of formula (X):

with a compound of formula (XI):

wherein L is a displaceable group;Process 7): for compounds of formula (I) wherein X is selected from —O—,—NR^(x)— and —S(O)_(a)— wherein a is 0; reacting a compound of formula(XII):

wherein L is a displaceable group; with a compound of formula (XIII):

Process 8): for compounds of formula (I) wherein X is selected from —O—,—NR^(x)— and —S(O)_(a)— wherein a is 0; reacting a compound of formula(XIV):

with a compound of formula (XV):

wherein L is a displaceable group;Process 9): for compounds of formula (I) wherein Y is selected from —O—,—NR^(z)— and —S(O)_(a)— wherein a is 0; reacting a compound of formula(XVI):

with a compound of formula (XVII):

wherein L is a displaceable group;Process 10): for compounds of formula (I) wherein Y is selected from—O—, —NR^(z)— and —S(O)_(a)— wherein a is 0; reacting a compound offormula (XVIII):

wherein L is a displaceable group; with a compound of formula (XIX):

Process 11): for compounds of formula (I) wherein X or Y is —S(O)_(a)—and a is 1 or 2; oxidizing a compound of formula (I) Wherein X or Y is—S(O)_(a)— and a is 0 (for compounds of formula (I) wherein and a is 1or 2) or a is 1 (for compounds of formula (I) wherein and a is 2);and thereafter if necessary or desirable:i) converting a compound of the formula (I) into another compound of theformula (I);ii) removing any protecting groups;iii) forming a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug; oriv) separating two or more enantiomers.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluenesulphonyloxy group.

Specific reaction conditions for the above reactions are as follows.Process 1): Alcohols of formula (II) may be reacted with compounds offormula (III) in the presence of a base for example an inorganic basesuch as sodium carbonate, or an organic base such as Hunigs base, in thepresence of a suitable solvent such as acetonitrile, dichloromethane ortetrahydrofuran at a temperature in the range of 0° C. to reflux,preferably at or near reflux.

Compounds of formula (II wherein X is —CR²R³—, Y is selected from—CR⁴R⁵—, R² and R³ together form an oxo group and R⁴ and R⁵ are bothhydrogen; may be prepared according to the following scheme:

Followed by removal of the benzyl protecting group.

Compounds of formula (II) with different values of X and Y may beprepared by the above scheme, but with modifications that would be knownto the skilled man. For example compound (IIh) could be modified to giveother values of R² and R³ or compound (IId) could be substituted for analternative compound that had the desired functionality, this compoundcould potentially include Ring A.

Compounds of formula (III) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art. Process 2), Process 3), Process 4) and Process 5):Acids and amines may be coupled together in the presence of a suitablecoupling reagent. Standard peptide coupling reagents known in the artcan be employed as suitable coupling reagents, for examplecarbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in thepresence of a catalyst such as dimethylaminopyridine or4-pyrrolidinopyridine, optionally in the presence of a base for exampletriethylamine, pyridine, or 2,6 di-alkyl-pyridines such as 2,6-lutidineor 2,6-di-tert-butylpyridine. Suitable solvents includedimethylacetamide, dichloromethane, benzene, tetrahydrofuran anddimethylformamide. The coupling reaction may conveniently be performedat a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for exampleacid chlorides, and active esters, for example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

Acids of formula (IV) and (VII) may be prepared from compounds offormula (II) by reacting them with the appropriate, optionallyprotected, side chain using the conditions of Process 1).

Amines of formula (V), (VI), (VII) and (IX) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Process 6): Compounds of formula (X) may be reacted with compounds offormula (XI) in the presence of a base for example an inorganic basesuch as sodium carbonate, or an organic base such as Hunigs base, in thepresence of a suitable solvent such as acetonitrile, dichloromethane,DMF or tetrahydrofuran at a temperature in the range of 0° C. to reflux,preferably at or near reflux. Alternatively this reaction may beperformed using transition metal chemistry known to the skilled person,for example copper or palladium chemistry.

Compounds of formula (X) may be prepared according to Scheme 1 with asuitable replacement for compound (IIb), for example benzylamine,followed by debenzylation at an appropriate point in the syntheticscheme.

Compounds of formula (XI) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art. Process 7), Process 8), Process 9) and Process 10):these compounds may be reacted together in the presence of a base forexample an inorganic base such as sodium carbonate, or an organic basesuch as Hunigs base, in the presence of a suitable solvent such asacetonitrile, dichloromethane or tetrahydrofuran at a temperature in therange of 0° C. to reflux, preferably at or near reflux.

Compounds of formula (XII), (XIV), (XVI) and (XVIII) may be preparedaccording to Scheme 1 with a suitable replacement for compound (IId).

Compounds of formula (XIII), (XV), (XVII) and (XIX) are commerciallyavailable compounds, or they are known in the literature, or they areprepared by standard processes known in the art.

Process 11): These compounds may be oxidised under standard sulphuroxidation conditions; for example using hydrogen peroxide andtrifluoroacetic acid at a temperature in the range of 0° C. to reflux,preferably at or near room temperature.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1999). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossess cholesterol absorption inhibitory activity These properties maybe assessed, using the following biological test.

In Vivo Testing of Cholesterol Absorption Inhibitors

C57BL/6 female mice were maintained on regular chow diet and housed inindividual cages to collect faeces. Mice were fasted for 3 hours andthen gavaged with vehicle or compound. Half an hour later the mice weregavaged with radiolabelled cholesterol. Two or six hours after the¹⁴C-cholesterol gavage blood samples were taken via the tail and plasmaprepared to determine how much cholesterol were absorbed. 24 hours afterthe gavage of ¹⁴C-cholesterol the mice were bled to death and plasmawere prepared for analysis. Faeces were collected for 24 hours to assessabsorption efficiency.

References

1. E. A. Kirk, G. L. Moe, M. T. Caldwell, J. Å. Lernmark, D. L. Wilson,R. C. LeBoeuf. Hyper- and hypo-responsiveness to dietary fat andcholesterol among inbred mice: searching for level and variabilitygenes. J. Lipid Res. 1995 36:1522-1532.

2. C. P. Carter, P. N. Howles, D. Y. Hui. Genetic variation incholesterol absorption efficiency among inbred strains of mice. J. Nutr.1997 127:1344-1348.

3. C. D. Jolley, J. M. Dietschy, S. D. Turley. Genetic differences incholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterolresponsiveness. Am. J. Physiol. 1999 276:G1117-G1124.

Absorption

The absorption of the compounds of formula (I) was tested in a Caco-2cells model (Gastroenterology 1989, 96, 736).

The data below shoes that Example 24 shows much lower absorptioncompared with ezetimibe (US RE37721).

Compound Example 24 Ezetimibe Apparent partition coefficient; P_(app)[cm/s] 0.24 × 10⁻⁰⁶ 21 × 10⁻⁰⁶

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, will normally beadministered to a warm-blooded animal at a unit dose within the range ofapproximately 0.02-100 mg/kg, preferably 0.02-50 mg/kg, and thisnormally provides a therapeutically-effective dose. A unit dose formsuch as a tablet or capsule will usually contain, for example 1-250 mgof active ingredient. Preferably a daily dose in the range of 1-50mg/kg, particularly 0.1-10 mg/kg is employed. In another aspect a dailydose in the rage of 0.01-20 mg/kg is employed. However the daily dosewill necessarily be varied depending upon the host treated, theparticular route of administration, and the severity of the illnessbeing treated. Accordingly the optimum dosage may be determined by thepractitioner who is treating any particular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, are effective cholesterol absorption inhibitors, andaccordingly have value in the treatment of disease states associatedwith hyperlipidaemic conditions.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in theproduction of a cholesterol absorption inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the production of a cholesterol absorption inhibitoryeffect in a warm-blooded animal, such as man.

Herein, where the production of a cholesterol absorption inhibitoryeffect or a cholesterol lowering effect is stated, suitably this relatesto the treatment of hyperlipidaemic conditions in a warm-blooded animal,such as man. Additionally is relates to the treatment of dyslipidemicconditions and disorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL) in awarm-blooded animal, such as man. Furthermore it relates to thetreatment of different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocytes, monocytes and/or macrophage infiltration, intimalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks in a warm-bloodedanimal, such as man. It also relates to the treatment ofatherosclerosis, coronary heart diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, stroke and transient ischaemicattacks in a warm-blooded animal, such as man.

The production of a cholesterol absorption inhibitory effect or acholesterol lowering effect also relates to a method of treating and/orpreventing atherosclerotic lesions, a method of preventing plaquerupture and a method of promoting lesion regression. Furthermore itrelates to a method of inhibiting monocytes-macrophage accumulation inatherosclerotic lesions, a method of inhibiting expression of matrixmetalloproteinases in atherosclerotic lesions, a method of inhibitingthe destabilization of atherosclerotic lesions, a method for preventingatherosclerotic plaque rupture and a method of treating unstable angina

The production of a cholesterol absorption inhibitory effect or acholesterol lowering effect also relates to a method of treatingsitosterolemia.

Compounds of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof may also have valuein the treatment or prevention of Alzeheimer's Disease (see for exampleWO 02/096415). Therefore in a further aspect of the invention, there isprovided a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, for use inthe treatment or prevention of Alzeheimer's Disease.

Compounds of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof may also have valuein the treatment or prevention of vascular inflammation (see for exampleWO 03/026644). Therefore in a further aspect of the invention, there isprovided a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, for use inthe treatment or prevention of vascular inflammation.

According to a further feature of this aspect of the invention there isprovided a method for producing a cholesterol absorption inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

The cholesterol absorption inhibitory activity defined hereinbefore maybe applied as a sole therapy or may involve, in addition to a compoundof the invention, one or more other substances and/or treatments. Suchconjoint treatment may be achieved by way of the simultaneous,sequential or separate administration of the individual components ofthe treatment. According to this aspect of the invention there isprovided a pharmaceutical product comprising a compound of the formula(I), or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof, as defined hereinbefore and an additionalcholesterol absorption inhibitory substance as defined hereinbefore andan additional hypolipidaemic agent for the conjoint treatment ofhyperlipidaemia.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with cholesterolbiosynthesis inhibitors, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable cholesterolbiosynthesis inhibitors include HMG Co-A reductase inhibitors, squalenesynthesis inhibitors and squalene epoxidase inhibitors. A suitablesqualene synthesis inhibitor is squalestatin 1 and a suitable squaleneepoxidase inhibitor is NB-598.

In this aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an HMG Co-Areductase inhibitor, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductaseinhibitors, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are statins well known in the art.Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and rosuvastatin, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof. A furtherparticular statin is pitvastatin, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof. A particularstatin is atorvastatin, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof. A more particular statin isatorvastatin calcium salt. A further particular statin is rosuvastatin,or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof. A preferable particular statin is rosuvastatincalcium salt.

Therefore in an additional feature of the invention, there is provided acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of an HMG Co-A reductaseinhibitor, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;

b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof; in a secondunit dosage form; and

c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;

b) an HFG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a secondunit dosage form; and

c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of a cholesterol lowering effect.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an H-MG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofa matrix metalloproteinase inhibitor.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an ileal bileacid (IBAT) inhibitor or a pharmaceutically acceptable salt solvate,solvate of such a salt or a prodrug thereof. Suitable compoundspossessing such IBAT inhibitory activity have been described, see forinstance hypolipidaemic compounds described in WO 93/16055, WO 94/18183,WO 94/18184, WO 96/05188, WO 96/08484, WO 15 96/16051, WO 97/33882, WO98/38182, WO 99/35135, WO 98/40375, WO 99/64409, WO 99/64410, WO00/01687, WO 00/47568, WO 00/61568, DE 19825804, WO 00/38725, WO00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/66533, WO02/50051 and EP 0 864 582 and the compound described in these patentapplications, particularly claim 1, are incorporated herein byreference.

Further suitable compounds possessing IBAT inhibitory activity have beendescribed in WO 94/24087, WO 98/07749, WO 98/56757, WO 99/32478, WO99/35135, WO 00/20392, WO 00/20393, WO 00/20410, WO 00/20437, WO01/34570, WO 00/35889, WO 01/68637, WO 01/68096, WO 02/08211, WO03/020710, WO 03/022825, WO 03/022830, WO 03/022286, JP 10072371, U.S.Pat. No. 5,070,103, EP 251 315, EP 417 725, EP 489 423, EP 549 967, 25EP 573 848, EP 624 593, EP 624 594, EP 624 595, EP 869 121 and EP 1 070703, and the contents of these patent applications, particularly thecompounds described in claim 1 and the named examples, are incorporatedherein by reference.

Particular classes of IBAT inhibitors suitable for use in the presentinvention are benzothiepines. Other suitable classes of IBAT inhibitorsare the 1,2-benzothiazepines, 1,4-benzothiazepines and/or1,5-benzothiazepines. A further suitable class of IBAT inhibitors is the1,2,5-benzothiadiazepines.

One particular suitable compound possessing IBAT inhibitory activity is(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ylβ-D-glucopyranosiduronic acid (EP 864 582).

A further suitable compound possessing IBAT inhibitory activity isS-8921 (EP 597 107).

A further suitable IBAT inhibitor is the compound:

Other particular suitable compound possessing IBAT inhibitory activityinclude:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbarmoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyI)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;and

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Additional suitable IBAT inhibitors for combination with compounds ofthe present invention are those described in WO 03/020710. Furthersuitable compounds possessing IBAT inhibitory activity have thefollowing structure of formula (AI):

wherein:

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁴ and R⁵ is a group of formula (AIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N-(C₁₋₆alkyl)sulphamoyl and N,N-(C₁₋₆alkyl)₂sulphamoyl; wherein R³ andR⁶ and the other of R⁴ and R⁵ may be optionally substituted on carbon byone or more R¹⁷;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedon carbon by one or more substituents selected from R¹⁸;

R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁰;

R⁸ is hydrogen or C₁₋₆alkyl;

R⁹ is hydrogen or C₁₋₆alkyl;

R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino, N,N,N-(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁰is optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (AIB):

wherein:

R¹¹ is hydrogen or C₁₋₆alkyl;

R¹² and R¹³ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl or heterocyclyl; whereinR¹² and R¹³ may be independently optionally substituted on carbon by oneor more substituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁶;

R¹⁴ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (AIC):

R¹⁵ is hydrogen or C₁₋₆alkyl;

R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶ may be optionally substitutedon carbon by one or more groups selected from R³¹;

n is 1-3; wherein the values of R⁷ may be the same or different;

R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independently selected fromhalo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino,N,N-(C₁₋₁₀alkyl)₂amino, N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino,N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a)wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵;

R²¹, R²², R²⁷, R²⁸, R³² or R³³ are independently selected from —O—,—NR³⁶—, —S(O)_(x)—, —NR³⁶C(O)NR³⁶—, —NR³⁶C(S)NR³⁶—, —OC(O)N═C—,—NR³⁶C(O)— or —C(O)NR³⁶-; wherein R³⁶ is selected from hydrogen orC₁₋₆alkyl, and x is 0-2;

p, q, r and s are independently selected from 0-2;

R³⁴ is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino,nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,formyl, acetyl, formamido, acetylamino, acetoxy, methylamino,dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio,methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl,N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;

R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl,C¹⁻⁶alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.

A particular IBAT inhibitor is selected from any one of Examples 1-44 ofWO 03/020710, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-44 areincorporated herein by reference. Claims 1-10 of WO 03/020710 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/020710 is selected from any one of:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(hydroxycarbamoyl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-{(R)-α-{N′-[2-(N′-pyrimidin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[2-(N′-pyridin-2-ylureido)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(1-t-butoxycarbonylpiperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2,3-dihydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[2-(3,4-dihydroxyphenyl)-2-methoxyethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(piperidin-4-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-N,N-dimethylaminosulphamoylethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Additional suitable MBAT inhibitors for combination with compounds ofthe present invention are those described in WO 03/022825. Furthersuitable compounds possessing IBAT inhibitory activity have thefollowing structure of formula (BI):

wherein:

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(y) is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₄alkoxy andC₁₋₆alkanoyloxy;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁴ and R⁵ is a group of formula (BIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (BIB):

wherein:

Y is —N(R^(x))—, —N(R^(x))C(O)—, —O—, and —S(O)_(a)—; wherein a is 0-2and R^(x) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R)^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1-3; wherein the values of R¹³ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁴ may be the same or different;

m is 0-2; wherein the values of R¹⁰ may be the same or different;

n is 1-3; wherein the values of R⁷ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹:

R¹⁹ and R²⁰ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl,N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may beindependently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

A particular IBAT inhibitor is selected from any one of Examples 1-7 ofWO 03/022825, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-7 areincorporated herein by reference. Claims 1-8 of WO 03/022825 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/022825 is selected from any one of:

1,1-dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine;

1,1-dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-[N-(R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine;

1,1-dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;

1,1-dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl)}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-(S)-3ethyl-3-butyl-4-hydroxy-5-(S)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

3,5-trans-1,1-dioxo-3-(R)-3-ethyl-3-butyl-4-hydroxy-5-(R)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepineammonia salt;

1,1-dioxo-3-(S)-3-ethyl-3-butyl-5-(S)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepinediethylamine salt; and

1,1-dioxo-3-(R)-3-ethyl-3-butyl-5-(R)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepinediethylamine salt;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Additional suitable IBAT inhibitors for combination with compounds ofthe present invention are those described in WO 03/022830. Furthersuitable compounds possessing IBAT inhibitory activity have thefollowing structure of formula (CI):

wherein:

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆-alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁴ and R⁵ is a group of formula (CIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C2-4alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (CIB):

wherein:

Y is —N(R^(n))—, —N(R^(n))C(O)—, —O—, and —S(O)_(a)—; wherein a is 0-2and R^(n) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1-3; wherein the values of R¹³ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁴ may be the same or different;

m is 0-2; wherein the values of R¹⁰ may be the same or different;

n is 1-3; wherein the values of R⁷ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C¹⁻⁴alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹ and R²⁰ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl,N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may beindependently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

A particular IBAT inhibitor is selected from any one of Examples 1-4 ofWO 03/022830, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-4 areincorporated herein by reference. Claims 1-8 of WO 03/022830 are alsoincorporated herein by reference. A particular IBAT inhibitor selectedfrom WO 03/022830 is selected from any one of:

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepineammonia salt

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[α-(carboxy)-2-fluorobenzyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine;and

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{(N-[1-(carboxy)-1-(thien-2-yl)methyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepineor a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Additional suitable IBAT inhibitors for combination with compounds ofthe present invention are those described in WO 03/022286. Furthersuitable compounds possessing IBAT inhibitory activity have thefollowing structure of formula (DI):

wherein:

R^(v) is selected from hydrogen or C₁₋₆alkyl;

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

M is selected from —N— or —CH—;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁴ and R⁵ is a group of formula (DIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶.

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆allyl; or R¹¹ is agroup of formula (DIB) or (DIC):

wherein:

Y is —N(R^(a))—, —N(R^(a))C(O)—,—N(R^(a))C(O)(CR^(s)R^(t))_(v)N(R^(n))C(O)—, —O—, and S(O)_(a)—; whereina is 0-2, v is 1-2, R^(s) and R^(t) are independently selected fromhydrogen or C₁₋₄alkyl optionally substituted by R²⁶ and R^(n) ishydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; and when q is 0, R¹⁴ may additionally beselected from hydroxy; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f))(whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1-3; wherein the values of R¹³ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁴ may be the same or different;

m is 0-2; wherein the values of R¹⁰ may be the same or different;

n is 1-3; wherein the values of R⁷ may be the same or different;

Ring B is a nitrogen linked heterocyclyl substituted on carbon by onegroup selected from R²³, and optionally additionally substituted oncarbon by one or more R²⁴; and wherein if said nitrogen linkedheterocyclyl contains an —NH— moiety, that nitrogen may be optionallysubstituted by a group selected from R²⁵;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²⁴ and R²⁶ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, benzyloxycarbonylamino, sulpho, sulphino, amidino,phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selectedfrom C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²⁴ and R²⁶ may be independentlyoptionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

R²³ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(g))(OR^(h)),—P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) whereinR^(g) and R^(h) are independently selected from C₁₋₆alkyl;

R²⁵ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆-alkoxycarbonyl, carbamoyl, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

A particular IBAT inhibitor is selected from any one of Examples 1-39 ofWO 03/022286, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, and the compounds of Examples 1-39 areincorporated herein by reference. Claims 1-10 of WO 03/022286 are alsoincorporated herein by reference. A particular MBAT inhibitor selectedfrom WO 03/022286 is selected from any one of:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;and

1,1dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Further suitable compounds possessing IBAT inhibitory activity have thefollowing structure of formula (EI):

wherein:

R^(v) is selected from hydrogen or C₁₋₆alkyl;

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆-alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O), wherein a is to 2;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁴ and R⁵ is a group of formula (EIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆-alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁷;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedon carbon by one or more substituents selected from R¹⁸;

R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁰;

R⁸ is hydrogen or C₁₋₆alkyl;

R⁹ is hydrogen or C₁₋₆alkyl;

R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₆alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino, N,N,N-(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁰is optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from

R²⁴; or R¹⁰ is a group of formula (EIB):

wherein:

R¹¹ is hydrogen or C₁₋₆alkyl;

R¹² and R¹³ are independently selected from hydrogen, halo, carbamoyl,sulphamoyl, C₁₋₁₀alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀alkanoyl,N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a)wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl or heterocyclyl; whereinR¹² and R¹³ may be independently optionally substituted on carbon by oneor more substituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁶;

R¹⁴ is selected from hydrogen, halo, carbamoyl, sulphamoyl,hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkanoyl, N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (EIC):

R¹⁵ is hydrogen or C₁₋₆alkyl;

R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶ may be optionally substitutedon carbon by one or more groups selected from R³¹;

n is 1-3; wherein the values of R⁷ may be the same or different;

R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independently selected fromhalo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino,N,N-(C₁₋₁₀alkyl)₂amino, N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino,N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a)wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹,R²³, R²⁵, R²⁹ or R³¹ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵;

R²¹, R²², R²⁷, R²⁸, R³² or R³³ are independently selected from —O—,—NR³⁶—, —S(O)_(x)—, —NR³⁶C(O)NR³⁶—, —NR³⁶C(S)NR³⁶—, —OC(O)N═C—,—NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ is selected from hydrogen orC₁₋₆alkyl, and x is 0-2;

p, q, r and s are independently selected from 0-2;

R³⁴ is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino,nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,formyl, acetyl, formamido, acetylamino, acetoxy, methylamino,dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio,methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl,N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;

R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl,C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N-(C₁₋₆alkyl)carbamoyl, N,N-(C¹⁻⁶alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Suitable IBAT inhibitors having the above structure are selected fromany one of:

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(both enantiomers);

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N-{2-(S)-[N-(carbamoylmethyl)carbamoyl]pyrrolidin-1-ylcarbonylmethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[2-(3,4,5-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(R)-3-(S)4-(S)-5-(R)-3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Further suitable compounds possessing IBAT inhibitory activity have thefollowing structure of formula (FI):

wherein:

R¹ and R² are independently selected from C₁₋₄alkyl;

R³ is hydrogen, hydroxy or halo;

R⁴ is C₁₋₄alkyl optionally substituted by hydroxy, methoxy andmethylS(O)_(a) wherein a is 0-2

R⁵ is hydroxy or HOC(O)CH(R⁶)NH—;

R⁶ is selected from hydrogen and C₁₋₃alkyl optionally substituted byhydroxy, methoxy and methylS(O)_(a) wherein a is 0-2;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof; with the proviso that when R¹ and R² are bothbutyl, R⁵ is hydroxy and R⁴ is methylthiomethyl, methylsulphinylmethyl,methylthiomethyl, hydroxymethyl, methoxymethyl; R³ is not hydrogen; andwith the proviso that when R¹ and R² are both butyl, R⁵ isHOC(O)CH(R⁶)NH—, R⁶ is hydroxymethyl and R⁴ is hydroxymethyl; R³ is nothydrogen.

Suitable IBAT inhibitors having the above structure are selected fromany one of:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N!-((S)-1-carboxybutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-mesylethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-oxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-3-methylsulphonylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-3-mesylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxyethyl)carbamoyl]4hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-methylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′((S)-1-carboxy-3-methylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-methylthioethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′((S)-1-carboxy-2-methylsulphinylethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-mesylethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-2-methoxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-3-methylthiopropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-3-methylsulphonylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxy-3-mesylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine.

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Further suitable BAT inhibitors are those having the structure (GI):

wherein

M¹ is —CH₂— or —NR²¹—;

M² is —CR²²R²³— or —NR²⁴—; provided that if M¹ is —NR²¹-, M² is—CR²²R²³—;

One of R¹ and R² are selected from hydrogen, C₁₋₆alkyl or C₂₋₆alkenyland the other is selected from C₁₋₆alkyl or C₂₋₆alkenyl;

R³ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆-alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0-5;

one of R⁵ and R⁶ is a group of formula (GIA):

R⁴ and R⁷ and the other of R⁵ and R⁶ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₋₁₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R⁴ and R⁷ and the other of R⁵ and R⁶may be optionally substituted on carbon by one or more R²⁵;

Z is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

R⁸ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁸ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁶; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁷;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ and R¹¹ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; or R¹⁰ and R¹¹ together form C₂₋₆alkylene;wherein R¹⁰ and R¹¹ or R¹⁰ and R¹¹ together may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁸; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R²⁹;

R¹² is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹² maybe optionally substituted on carbon by one or more substituents selectedfrom R³⁰; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R³¹;

R¹³ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀ alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclic group, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R³²—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R³³—(C₁₋₁₀alkylene)_(h)-; wherein R¹³may be optionally substituted on carbon by one or more substituentsselected from R³⁶; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁷; or R¹³ is a group of formula (GIB):

wherein:

X is —N(R³⁸)—, —N(R³⁸)C(O)—, —O—, and —S(O)_(a)—; wherein a is 0-2 andR³⁸ is hydrogen or C₁₋₄alkyl;

R¹⁴ is hydrogen or C₁₋₄alkyl;

R¹⁵ and R¹⁶ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, carbocyclyl or heterocyclic group; whereinR¹⁵ and R¹⁶ may be independently optionally substituted on carbon by oneor more substituents selected from R⁴¹; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R⁴²;

R¹⁷ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl, C₁₋₁₀alkoxycarbonyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl, carbocyclylC₁₋₁₀alkyl, heterocyclic group,heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁴³—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁴⁴—(C₁₋₁₀alkylene)_(h)-; wherein R¹⁷may be optionally substituted on carbon by one or more substituentsselected from R⁴⁷; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R⁴⁸; or R¹⁷ is a group of formula (GIC):

wherein:

R¹⁸ is selected from hydrogen or C₁₋₄alkyl;

R¹⁹ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl,carbocyclyl or heterocyclic group; where R¹⁹ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R¹⁵; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R⁵²;

R²⁰ is selected from halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclic group, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁵³—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁵⁴—(C₁₋₁₀alkylene)_(h)-; wherein R²⁰may be independently optionally substituted on carbon by one or moreR⁵⁷; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R⁵⁸;

p is 1-3; wherein the values of R¹⁵ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁶ may be the same or different;

m is 0-2; wherein the values of R¹² may be the same or different;

n is 1-2; wherein the values of R⁸ may be the same or different;

z is 0-3; wherein the values of R¹⁹ may be the same or different;

R²¹ is selected from hydrogen or C₁₋₆alkyl;

R²² and R²³ are independently selected from hydrogen, hydroxy, amino,mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

R²⁴ is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₄alkoxy andC₁₋₆alkanoyloxy;

R²⁵ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O), wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R²⁵, may be independently optionallysubstituted on carbon by one or more R⁶⁷;

R²⁶, R²⁸, R³⁰, R³⁶, R⁴¹, R⁴⁷, R⁵¹ and R⁵⁷ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,C₁₋₁₀alkoxycarbonyl, N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino,N,N,N-(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclic group, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁵⁹—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁶⁰-(C₁₋₁₀alkylene)_(h)-; wherein R²⁶,R²⁸, R³⁰, R³⁶, R⁴¹, R⁴⁷, R⁵¹ and R⁵⁷ may be independently optionallysubstituted on carbon by one or more R⁶³; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R⁶⁴;

R²⁷, R²⁹, R³¹, R³⁷, R⁴², R⁴⁸, R⁵², R⁵⁸ and R⁶⁴ are independentlyselected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, sulphamoyl,N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkoxycarbonyl,carbamoyl, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, benzyl,phenethyl, benzoyl, phenylsulphonyl and phenyl;

R³², R³³, R⁴³, R⁴⁴, R⁵³, R⁵⁴, R⁵⁹ and R⁶⁰are independently selected from—O—, —NR⁶⁵—, —S(O)_(x)—, —NR⁶⁵C(O)NR⁶⁶—, —NR⁶⁵C(S)NR⁶⁶—, —OC(O)N═C—,—NR⁶⁵C(O)— or —C(O)NR⁶⁵-; wherein R⁶⁵ and R⁶⁶ are independently selectedfrom hydrogen or C₁₋₆alkyl, and x is 0-2;

R⁶³ and R⁶⁷ re independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido,acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,N-methylsulphamoyl and N,N-dimethylsulphamoyl; and

e, f, g and h are independently selected from 0-2;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Additional suitable IBAT inhibitors having the above structure areselected from any one of:

(+/−)-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;

(+/−)-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{R)-α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4benzothiazepine;

1,1-dioxo-3-ethyl-3-butyl-4-hydroxy-5-phenyl-7-(N-{α-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-2-fluorobenzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiapine;or

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{1-[N′-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-1-(cyclohexyl)methyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine.

Compounds of formula (AI), (BI), (CI), (DI), (EI), (FI) and (GI) or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof may be prepared by processes known in the art.

In a particular aspect of the invention an IBAT inhibitor or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof is an IBAT inhibitor or a pharmaceutically acceptablesalt thereof.

Therefore in an additional feature of the invention, there is provided acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of an IBAT inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an IBAT inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, inassociation with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;

b) an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof; in a second unit dosageform; and

c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;

b) an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in a second unit dosageform; and

c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an IBATinhibitor, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, in the manufacture of a medicament foruse in the production of a cholesterol lowering effect in a warm-bloodedanimal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an IBAT inhibitor, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a PPAR alphaand/or gamma agonist, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/orgamma agonists, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are well known in the art. These includethe compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39,665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (inparticular the compounds described in the patent applications listed onpage 634) and J Med Chem, 2000, 43, 527 which are all incorporatedherein by reference. Particularly a PPAR alpha and/or gamma agonistrefers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578,troglitazone, proglitazone, rosiglitazone, eglitazone, proglitazone,NN622/Ragaglitazar, BMS 298585, BRL-49634, KRP-297, JTT-501, SB 213068,GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. Particularlya PPAR alpha and/or gamma agonist refers to(S)-2-ethoxy-3-[4(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoicacid and pharmaceutically acceptable salts thereof.

Therefore in an additional feature of the invention, there is provided acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a PPAR alpha and/or gammaagonist, or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in a first unitdosage form;

b) a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof; in a secondunit dosage form; and

c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

a) a compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, together with apharmaceutically acceptable diluent or carrier, in a first unit dosageform;

b) a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, in a secondunit dosage form; and

c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in producing a cholesterol lowering effect in awarm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a nicotinicacid derivative or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof. As used herein “nicotinic acidderivative” means a compounds comprising a pyridine-3-carboxylatestructure or a pyrazine-2-carboxylate structure. Examples of nicotinicacid derivatives include nicotinic acid, niceritrol, nicofuranose,NIASPAN® and acipimox.

Therefore, in an additional feature of the invention, there is provideda combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a nicotinic acid derivative or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a nicotinic acid derivative,or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a nicotinic acid derivative, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a nicotinicacid derivative, or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof, in the manufacture of a medicamentfor use in the production of a cholesterol lowering effect in awarm-blooded animal, such as man.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a bile acidsequestrant or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof. Suitable bile acid sequestrantsinclude cholestyramine, cholestipol and cosevelam hydrochloride.

Therefore, in an additional feature of the invention, there is provideda combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a bile acid sequestrant or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a bile acid sequestrant, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid sequestrant, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a bile acidsequestrant, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, in the manufacture of a medicament foruse in the production of a cholesterol lowering effect in a warm-bloodedanimal, such as man.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from Group X:

-   -   an antihypertensive compound (for example althiazide,        benzthiazide, captopril, carvedilol, chlorothiazide sodium,        clonidine hydrochloride, cyclothiazide, delapril hydrochloride,        dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,        guanfacine hydrochloride, methyidopa, metoprolol succinate,        moexipril hydrochloride, monatepil maleate, pelanserin        hydrochloride, phenoxybenzemine hydrochloride, prazosin        hydrochloride, primidolol, quinapril hydrochloride, quinaprilat,        ramipril, terazosin hydrochloride, candesartan, candesartan        cilexetil, telmisartan, amlodipine besylate, amlodipine male ate        and bevantolol hydrochloride);    -   an angiotensin converting enzyme inhibitor (for example        alacepril, alatriopril, altiopril calcium, ancovenin,        benazepril, benazepril hydrochloride, benazeprilat,        benzoylcaptopril, captopril, captopril-cysteine,        captopril-glutathione, ceranapril, ceranopril, ceronapril,        cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril,        enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril,        fosenopril, fosenopril sodium, fosinopril, fosinopril sodium,        fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,        idrapril, imidapril, indolapril, indolaprilat, libenzapril,        lisinopril, lyciumin A, lyciumin B, mixanpril, moexipril,        moexiprilat, moveltipril, muracein A, muracein B, muracein C,        pentopril, perindopril, perindoprilat, pivalopril, pivopril,        quinapril, quinapril hydrochloride, quinaprilat, ramipril,        ramiprilat, spirapril, spirapril hydrochloride, spiraprilat,        spiropril, spiropril hydrochloride, temocapril, temocapril        hydrochloride, teprotide, trandolapril, trandolaprilat,        utibapril, zabicipril, zabiciprilat, zofenopril and        zofenoprilat);    -   an angiotensin II receptor antagonist (for example candesartan,        candesartan cilexetil, losartan, valsartan, irbesartan,        tasosartan, telmisartan and eprosartan);    -   an andrenergic blocker (for example bretylium tosylate,        dihydroergotamine so mesylate, phentolamine mesylate,        solypertine tartrate, zolertine hydrochloride, carvedilol or        labetalol hydrochloride); an alpha andrenergic blocker (for        example fenspiride hydrochloride, labetalol hydrochloride,        proroxan and alfuzosin hydrochloride); a beta andrenergic        blocker (for example acebutolol, acebutolol hydrochloride,        alprenolol hydrochloride, atenolol, bunolol hydrochloride,        carteolol hydrochloride, celiprolol hydrochloride, cetamolol        hydrochloride, cicloprolol hydrochloride, dexpropranolol        hydrochloride, diacetolol hydrochloride, dilevalol        hydrochloride, esmolol hydrochloride, exaprolol hydrochloride,        flestolol sulfate, labetalol hydrochloride, levobetaxolol        hydrochloride, levobunolol hydrochloride, metalol hydrochloride,        metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate,        penbutolol sulfate, practolol, propranolol hydrochloride,        sotalol hydrochloride, timolol, timolol maleate, tiprenolol        hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate and        nebivolol); or a mixed alpha/beta andrenergic blocker;    -   an andrenergic stimulant (for example combination product of        chlorothiazide and methyidopa, the combination product of        methyidopa hydrochlorothiazide and methyidopa, clonidine        hydrochloride, clonidine, the combination product of        chlorthalidone and clonidine hydrochloride and guanfacine        hydrochloride);    -   channel blocker, for example a calcium channel blocker (for        example clentiazem maleate, amlodipine besylate, isradipine,        nimodipine, felodipine, nilvadipine, nifedipine, teludipine        hydrochloride, diltiazem hydrochloride, belfosdil, verapamil        hydrochloride or fostedil);    -   a diuretic (for example the combination product of        hydrochlorothiazide and spironolactone and the combination        product of hydrochlorothiazide and triamterene);    -   anti-anginal agents (for example amlodipine besylate, amlodipine        maleate, betaxolol hydrochloride, bevantolol hydrochloride,        butoprozine hydrochloride, carvedilol, cinepazet maleate,        metoprolol succinate, molsidomine, monatepil maleate,        primidolol, ranolazine hydrochloride, tosifen or verapamil        hydrochloride);    -   vasodilators for example coronary vasodilators (for example        fostedil, azaclorzine hydrochloride, chromonar hydrochloride,        clonitrate, diltiazem hydrochloride, dipyridamole,        droprenilamine, erythrityl tetranitrate, isosorbide dinitrate,        isosorbide mononitrate, lidoflazine, mioflazine hydrochloride,        mixidine, molsidomine, nicorandil, nifedipine, nisoldipine,        nitroglycerine, oxprenolol hydrochloride, pentrinitrol,        perhexiline maleate, prenylamine, propatyl nitrate, terodiline        hydrochloride, tolamolol and verapamil);    -   anti-coagulants (selected from argatroban, bivalirudin,        dalteparin sodium, desirudin, dicumarol, lyapolate sodium,        nafamostat mesylate, phenprocoumon, tinzaparin sodium and        warfarin sodium);    -   antithrombotic agents (for example anagrelide hydrochloride,        bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium,        dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium,        fluretofen, ifetroban, ifetroban sodium, lamifiban, lotrafiban        hydrochloride, napsagatran, orbofiban acetate, roxifiban        acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab        and zolimomab aritox);    -   fibrinogen receptor antagonists (for example roxifiban acetate,        fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban,        xemilofiban, monoclonal antibody 7E3 and sibrafiban)    -   platelet inhibitors (for example cilostezol, clopidogrel        bisulfate, epoprostenol, epoprostenol sodium, ticlopidine        hydrochloride, aspirin, ibuprofen, naproxen, sulindae,        indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone        and piroxicam, dipyridamole);    -   platelet aggregation inhibitors (for example acadesine,        beraprost, beraprost sodium, ciprostene calcium, itezigrel,        lifarizine, lotrafiban hydrochloride, orbofiban acetate,        oxagrelate, fradafiban, orbofiban, tirofiban and xemilofiban)    -   hemorrheologic agents (for example pentoxifylline);    -   lipoprotein associated coagulation inhibitors;    -   Factor VIIa inhibitors;    -   Factor Xa inhibitors;    -   low molecular weight heparins (for example enoxaparin,        nardroparin, dalteparin, certroparin, parnaparin, reviparin and        tinzaparin);    -   squalene synthase inhibitors;    -   squalene epoxidase inhibitors;    -   liver X receptor (LXR) agonists for example GW-3965 and those        described in WO00224632, WO0103705, WO02090375 and WO00054759        (claim 1 and the named examples of these four application are        incorporated herein by reference);    -   microsomal triglyceride transfer protein inhibitors for example        implitapide and those described in WO03004020, WO03002533,        WO02083658 and WO 00242291 (claim 1 and the named examples of        these four application are incorporated herein by reference);        or a pharmaceutically acceptable salt, solvate, solvate of such        a salt or a prodrug thereof, optionally together with a        pharmaceutically acceptable diluent or carrier to a warm-blooded        animal, such as man in need of such therapeutic treatment.

Therefore, in an additional feature of the invention, there is provideda combination of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a compound from Group X or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing a cholesterol lowering effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof in simultaneous, sequential or separateadministration with an effective amount of a compound from Group X, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a compound from Group X, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,in association with a pharmaceutically acceptable diluent or carrier.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a compoundfrom Group X, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, in the manufacture of a medicament foruse in the production of a cholesterol lowering effect in a warm-bloodedanimal, such as man.

In addition to their use in therapeutic medicine, the compounds offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, are also useful as pharmacologicaltools in the development and standardisation of in vitro and in vivotest systems for the evaluation of the effects of inhibitors ofcholesterol absorption in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

Many of the intermediates described herein are novel and are thusprovided as a further feature of the invention. For example compounds offormula (IV) show cholesterol absorption inhibitory activity when testedin the above referenced in vitro test assay and are thus claimed as afurther feature of the invention.

Thus in a further feature of the invention, there is provided a compoundof formula (IV), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

Therefore according to a further aspect of the invention there isprovided a pharmaceutical composition which comprises a compound offormula (W), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, as defined hereinbefore in associationwith a pharmaceutically-acceptable diluent or carrier.

According to an additional aspect of the present invention there isprovided a compound of the formula (IV), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore for use in a method of prophylactic ortherapeutic treatment of a warm-blooded animal, such as man.

Thus according to this aspect of the invention there is provided acompound of the formula (IV), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (IV), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof as definedhereinbefore in the manufacture of a medicament for use in theproduction of a cholesterol absorption inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (IV), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof as definedhereinbefore in the manufacture of a medicament for use in the treatmentof hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing a cholesterol absorption inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (IV), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (a), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated in the following non limitingExamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these Examples may be usedwhere appropriate, and in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) all reactions were carried out under an inert atmosphere at ambienttemperature, typically. in the range 18-25° C., with solvents of HPLCgrade under anhydrous conditions, unless otherwise stated;

(iii) column chromatography (by the flash procedure) was performed onSilica gel 40-63 μm (Merck);

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the structures of the end products of the formula (I) were generallyconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; magnetic resonance chemical shift values weremeasured in deuterated CDCl₃ (unless otherwise stated) on the deltascale (ppm downfield from tetramethylsilane); proton data is quotedunless otherwise stated; spectra were recorded on a Varian Mercury-300MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz or on VarianInova-500 MHz spectrometer unless otherwise stated data was recorded at400 MHz; and peak multiplicities are shown as follows: s, singlet; d,doublet; dd, double doublet; t, triplet; tt, triple triplet; q, quartet;tq, triple quartet; m, multiplet; br, broad; ABq, AB quartet; ABd, ABdoublet, ABdd, AB doublet of doublets; dABq, doublet of AB quartets;LCMS were recorded on a Waters ZMD, LC column xTerra MS C₈(Waters),detection with a HP 1100 MS-detector diode array equipped; mass spectra(MS) (loop) were recorded on VG Platform II (Fisons Instruments) with aHP-1100 MS-25 detector diode array equipped; unless otherwise stated themass ion quoted is (MH⁺); unless further details are specified in thetext, analytical high performance liquid chromatography (HPLC) wasperformed on Prep LC 2000 (Waters), Cromasil C₈, 7 μm, (Akzo Nobel);MeCN and de-ionised water 10 mM ammonium acetate as mobile phases, withsuitable composition;(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), BPLC, infra-red (IR),MS or NMR analysis;(viii) where solutions were dried sodium sulphate was the drying agent;and(ix) the following abbreviations may be used hereinbefore orhereinafter:

DCM dichloromethane; DMF N,N-dimethylformamide; TBTUo-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium- tetrafluoroborate;EtOAc ethyl acetate; MeCN acetonitrile; TFA trifluoroacetic acid; IPAisopropanol; DIPEA di-isopropylethylamine; and THF tetrahydrofuran.

Example 11-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)phenyl]azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 1; 20 mg, 0.043 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]glycinate (Method 4; 14 mg, 0.047 mmol)and 2,6-lutidine (25 μl, 0.21 mmol) were added to DCM (2 ml) and themixture was stirred for 5 minutes. TBTU (18 mg, 0.056 mmol) was addedand the mixture was stirred for 4 hours at room temperature. Thereaction mixture was purified by column chromatography using DCM/EtOAc(10/2) as eluent to give 17 mg (56%) of the title compound. M/z 712.4(m−H)⁻.

Example 21-(4-Fluorophenyl)-3-[3-(4-fluorolphenyl)-3-hydroxypropyl]-4-[4-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)phenyl]azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)phenyl]azetidin-2-one(Example 1; 17 mg, 0.024 mmol) was added to formic acid (1 ml) and themixture was stirred for 2.5 hours at room temperature. The solvent wasevaporated under reduced pressure and methanol (1 ml) and triethylamine(75 μl) were added to the residue. The mixture was stirred for 4.5 hoursat room temperature and the solvents were evaporated under reducedpressure. The residue was solved in MeCN/water (50/50) (3 ml) and aceticacid (1 ml). The mixture was lyophilised to obtain 13 mg (83%) of thetitle compound. NMR (300 MHz, DMSO-d₆):1.65-1.85 (m, 4H), 3.05 (bs, 1H),3.5-3.7 (m, 3H), 4.45-4.55 (m, 1H), 4.6 (d, 2H), 4.85 (m, 1H), 5.55 (d,1H), 6.9 (d, 1H), 7.05-7.4 (m, 17H), 8.4-8.55 (m, 2H); m/z 656.2 (m−H)⁻.

Example 31-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4[N-((2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoylmethoxy]phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one (Method 1; 40 mg, 0.086 mmol), D-glucamine (16 mg,0.09 mmol) and 2,6-lutidine (50 μl, 0.42 mmol) were added to DCM (3 ml)and 2 drops of DMF. TBTU (36 mg, 0. 11 mmol) was added and the mixturewas stirred at room temperature for 2 hours. The solvents wereevaporated under reduced pressure and the residue was purified twice bypreparative HPLC using MeCN/ammonium acetate buffer (45:55) as eluent.The collected fractions were lyophilised to obtain 16 mg (30%) of thetitle compound. NMR (300 MHz, CD₃OD): 1.8-2.0 (m, 4H), 3.15-3.2 (m, 1H),3.4-4.0 (m, 8H), 4.6 (s, 2H), 4.7-4.8 (m, 1H), 4.9 (bs, 1H), 7.0-7.5 (m,12H); m/z 629.2 (m−H)⁻.

Example 41-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((R)-α-{N-(S)-[1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one (Method 1; 40 mg, 0.086 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate (Method 6;33 mg, 0.095 mmol) and 2,6-lutidine (50 μl, 0.42 mmol) were added to DCM(3 ml). TBTU (36 mg, 0.11 mmol) was added and the mixture was stirred atroom temperature for 7 hours. The solvents were evaporated under reducedpressure to give a mixture containing the title compound. M/z 798.4(M−H)⁻.

Example 51-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxyl)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

The1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(R)-α-{N-(S)-[1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-oneprepared in Example 4 was added to formic acid (3 ml) and the mixturewas stirred for 5 days at room temperature. The solvent was evaporatedunder reduced pressure and methanol (4 ml) and triethylamine (0.4 ml)were added to the residue. The mixture was stirred for 24 hours at roomtemperature and the solvents were evaporated under reduced pressure. Theresidue was purified by preparative HPLC using MeCN/ammonium acetatebuffer (40:60) as eluent. The collected fractions were lyophilised toobtain 12 mg (20%, 2 steps) of the title compound. NMR (300 MHz, CD₃OD):1.8-1.95 (m, 4H), 3.1 (bs, 1H), 3.7-3.8 (m, 2H), 4.35 (bs, 1H), 4.55-4.7(m, 3H), 4.8 (s, 1H), 5.65 (s, 1H), 6.95-7.4 (m, 17H); m/z 686.3 (m−H)⁻.

Example 61-(4-Fluorolphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-{N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoylmethoxy}phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one (Method 1; 40 mg, 0.086 mmol tert-butyl(2R)-amino(phenyl)acetate (20 mg, 0.095 mmol) and 2,6-lutidine (50 μl,0.42 mmol) were added to DCM (3 ml). TBTU (36 mg, 0.11 mmol) was addedand the mixture was stirred at room temperature for 5 hours. The solventwas evaporated under reduced pressure and was co-evaporated withtoluene. The residue was purified by column chromatography usingDCM/EtOAc (10/2) as eluent to give the title compound. M/z 655.3 (m−H)⁻.

Example 71-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(R)-α-(carboxy)benzyl]carbamoylmethoxy}phenyl)azetidin-2-one

The1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-{N-[R)-α-(t-butoxycarbonyl)benzyl]carbamoylmethoxy}phenyl}azetidin-2-oneprepared in Example 6 was added to formic acid (3 ml) and the mixturewas stirred for 12 hours at room temperature. The solvent was evaporatedunder reduced pressure and was co-evaporated with toluene. Methanol (3ml) and triethylamine (0.1 ml) were added to the residue and the mixturewas stirred for 4 hours at room temperature The solvents were evaporatedunder reduced pressure and the residue was purified by preparative HPLCusing MeCN/ammonium acetate buffer (50:50) as eluent. The collectedfractions were lyophilised to obtain 17 mg (33%, 2 steps) of the titlecompound. NMR (300 MHz, CD₃OD): 1.8-2.0 (m, 4H), 3.05-3.15 (m, 1H),4.5-4.7 (m, 3H), 4.8 (bs, 1H), 5.35 (d, 1H), 6.95-7.45 (m, 17H); m/z599.5 (m−H)⁻.

Example 81-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(t-butoxycarbonylmethyl)carbamoylmethoxy]phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one (Method 1; 40 mg, 0.086 mmol), glycinetert-butylester (18 mg, 0.091 mmol) and 2,6-lutidine (50 μl, 0.42 mmol)were added to DCM (3 ml). TBTU (36 mg, 0.11 mmol) was added and themixture was stirred at room temperature for 20 hours. The solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography using DCM/EtOAc (10/4) as eluent to give the titlecompound, M/z 579.2 (m−H)⁻.

Example 91-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one

The1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(t-butoxycarbonylmethyl)carbamoylmethoxy]phenyl}azetidin-2-oneprepared in Example 8 was added to formic acid (3 ml) and the mixturewas stirred for 4 hours at room temperature. The solvent was evaporatedunder reduced pressure and was co-evaporated with toluene. Methanol (3ml) and triethylamine (0.1 ml) were added to the residue and mixture wasstirred for 20 hours at room temperature The solvents were evaporatedunder reduced pressure and the residue was purified by preparative HPLCusing MeCN/ammonium acetate buffer (45:55) as eluent. The collectedfractions were lyophilised to obtain 14 mg (31%, 2 steps) of the titlecompound. NMR (300 MHz, CD₃OD): 1.8-2.0 (m, 4H), 3.05-3.15 (m, 1H), 3.85(s, 2H), 4.55 (s, 2H), 4.6-4.7 (m, 1H), 4.8 (bs, 1H), 6.95-7.35 (m, 12H); m/z 523.1 (m−H)⁻.

Example 101-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 8; 0.050 g, 0.110 mmol), tert-butylglycinate hydrochloride (0.022 g, 0.131 mmol) and N-methylmorpholine(0.050 ml, 0.454 mmol) in DCM (3 ml) was stirred at room temperature for5 minutes, after which TBTU (0.046 g, 0.143 mmol) was added. After 78hours the conversion to the ester (m/z: 567.2) was completed and thesolvent was removed under reduced pressure. The residue was dissolved informic acid (3 ml) and the solution was stirred for 20 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammoniumacetate buffer as eluent. The fractions were freeze-dried and the titlecompound was obtained as a white solid (0.056 g; ˜quantitative yield).NMR (CD₃OD, 400 MHz) 2.25-2.40 (m, 2H), 3.25-3.35 (m, 1H), 3.90.(s, 2H),4.05-4.20 (m, 2H),4.50 (s, 2H) 5.00 (d, 1H), 6.80-7.05 (m, 8H),7.25-7.40 (m, 4H); m/z: 511.1.

Example 111-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-(4-{N-[(R)-α-(carboxy)-4-(hydroxy)benzyl]carbamoylmethoxy}phenyl)azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 8; 0.070 g, 0.154 mmol), tert-butylD-tyrosinate (0.044 g, 0.185 mmol) and N-methylmorpholine (0.051 ml,0.463 mmol) in DCM (5 ml) was stirred at room temperature for 5 minutes,after which TBTU (0.065 g, 0.202 mmol) was added. After 20 hours, theconversion to the ester (m/z: 673.4) was complete and the solvent wasremoved under reduced pressure. The residue was dissolved in formic acid(5 ml) and the solution was stirred for 24 hours. The solvent wasremoved under reduced pressure and the residue was purified bypreparative IPLC using a gradient of 20-50% MeCN in 0. 1M ammoniumacetate buffer as eluent. The fractions were freeze-dried and the titlecompound was obtained as a white solid (0.052 g; 55%). NMR (CD₃OD, 400MHz) 2.25-2.40 (m, 2H), 2.85-3.15 (m, 2H), 3.25-3.40 (m, 1H), 4.05-4.20(m, 2H), 4.35-4.50 (m, 2H), 4.55-4.65 (m, 1H), 5.00 (d, 1H), 6.55-6.65(m, 2H), 6.80-7.05 (m, 10H), 7.25-7.35 (m, 4H); m/z: 615.2 (M−H)⁻.

Example 121-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-(4-{N-[(R)-1-(carboxy)-2-(hydroxy)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 8; 0.070 g, 0.154 mmol), tert-butylO-(tert-butyl)-D-serinate hydrochloride (0.047 g, 0.185 mmol) andN-methylmorpholine (0.068 ml, 0.617 mmol) in DCM (5 ml) was stirred atroom temperature for 5 minutes, after which TBTU (0.065 g, 0.202 mmol)was added. After 20 hours, the conversion to the ester (m/z: 653.4) wascompleted and TFA (1.5 ml) was added to the reaction mixture. After 24hours the solvent was removed under reduced pressure and the residue waspurified by preparative HPLC, using a gradient of 20-50% MeCN in 0. 1Mammonium acetate buffer as eluent. The fractions were freeze-dried andthe title compound was obtained as a white solid (0.074 g; 89%). M/z:541.1. NMR (CD₃OD, 400 MHz) 2.25-2.40 (m, 2H), 3.25-3.35 (m, 1H),3.80-3.95 (m, 2H), 4.05-4.20 (m, 2H), 4.40 (t, 1H), 4.55 (s, 2H), 5.00(d, 1H), 6.80-6.90 (m, 2H), 6.90-7.05 (m, 6H), 7.25-7.40 (m, 4H).

Example 131-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-{4-[N-((R)-1-carboxy-3-methylbutyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 8; 0.070 g, 0.154 mmol), tert-butyl D-leucinate hydrochloride(0.042 g, 0.188 mmol) and N-methylmorpholine (0.068 ml, 0.617 mmol) inDCM (5 ml) was stirred at room temperature for 5 minutes, after whichTBTU (0.065 g, 0.202 mmol) was added. After 20 hours, the conversion tothe ester (m/z: 623.3) was complete and the solvent was removed underreduced pressure. The residue was dissolved in formic acid (5 ml) andthe solution was stirred for 20 hours. The solvent was removed underreduced pressure and the residue was purified by preparative BPLC usinga gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. Thefractions were freeze-dried and the title compound was obtained as awhite solid (0.080 g; 91%). NMR (DMSO, 400 MHz) 0.75-0.85 (m, 6H),1.45-1.60 (m, 3H), 2.15-2.30 (m, 2H), 3.20-3.30 (m, 1H), 4.00-4.25 (m,3H), 4.50 (ABq, 2H), 5.05 (d, 1H), 6.85-6.95 (m, 4H), 7.00-7.25 (m, 6H),7.30-7.40 (m, 2H), 8.05 (t, 1H); m/z: 567.3.

Example 141-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-(4-{N-[(S)-1-(carboxy)-3-(carbamoyl)propyl]carbamoylmethoxy}phenyl)azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 8; 0.070 g, 0.154 mmol), tert-butylL-glutaminate hydrochloride (0.044 g, 0.184 mmol) and N-methylmorpholine(0.068 ml, 0.617 mmol) in DCM (5 ml) was stirred at room temperature for5 minutes, after which TBTU (0.065 g, 0.202 mmol) was added. After 20hours, the conversion to the ester (m/z: 638.3) was complete and thesolvent was removed under reduced pressure. The residue was dissolved informic acid (5 ml) and the solution was stirred for 20 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammoniumacetate buffer as eluent. The fractions were freeze-dried and the titlecompound was obtained as a white solid (0.088 g; 98%). NMR (CD₃OD, 400MHz) 1.90-2.40 (m, 6H), 3.25-3.35 (m, 1H), 4.05-4.20 (m, 2H), 4.30-4.40(m, 1H), 4.50 (s, 2H), 5.00 (d, 1H), 6.80-7.05 (m, 8H), 7.25-7.40 (m,4H); m/z: 582.2.

Example 151-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 8; 0.051 g, 0.113 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate (Method 6;0.047 g, 0.134 mmol) and N-methylmorpholine (0.050 ml, 0.454 mmol) inDCM (5 ml) was stirred at room temperature for 10 minutes, after whichTBTU (0.065 g, 0.202 mmol) was added. After 18 hours, the conversion tothe ester (m/z: 786.5) was complete and TFA (1.5 ml) was added to thereaction mixture. After 24 hours the solvent was removed under reducedpressure and the residue was purified by preparative HPLC using agradient of 30-50% MeCN in 0.1M ammonium acetate buffer as eluent. Thefractions were freeze-dried and the title compound was obtained as awhite solid (0.057 g; 75%). NMR (CD₃OD, 400 MHz) 2.25-2.40 (m, 2H),3.25-3.35 (m, 1H), 3.65-3.85 (m, 2H), 4.05-4.20 (m, 2H), 4.30-4.40 (m,1H), 4.50-4.65 (m, 2H), 5.00 (d, 1H), 5.65 (s, 1H), 6.80-7.05 (m, 8H),7.20-7.45 (m, 9H); m/z: 674.2.

Example 16.1-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-{4-[N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]phenyl}azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 8; 0.050 g, 0.110 mmol),(R)-α-{N-[(S)-1-(t-butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamine(Method 11 of WO 03/022286; 0.046 g, 0.133 mmol) and N-methylmorpholine(0.049 ml, 0.445 mmol) in DCM (5 ml) was stirred at room temperature for10 minutes, after which TBTU (0.046 g, 0.143 mmol) was added. After 20hours, the conversion to the ester (m/z: 744.5) was completed and thesolvent was removed under reduced pressure. The residue was dissolved informic acid (3 ml) and the solution was stirred for 24 hours before thesolvent again was removed under reduced pressure. The residue waspurified by preparative HPLC using a gradient of 30-50% MeCN in 0.1Mammonium acetate buffer as eluent. The fractions were freeze-dried andthe title compound was obtained as a white solid (0.052 g; 69%). NMR(CD₃OD, 400 MHz) 0.70-0.80.(m, 3H), 1.55-1.70 (m, 1H), 1.75-1.90 (m,1H), 2.25-2.40 (m, 2H), 3.25-3.35 (m, 1H), 4.05-4.20 (m, 2H), 4.20-4.30(m, 1H), 4.55 (ABq, 2H), 5.00 (d, 1H), 5.50 (d, 1H), 6.65-6.75 (m, 2H),6.80-7.05 (m, 8H), 7.15-7.40 (m, 6H); m/z: 688.2.

Example 173-(R)-4-(R)-1-(Phenyl)-3-(phenylethylsulphanyl)-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(phenylethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 9; 0.050 g, 0.115 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate (Method 6;0.049 g, 0.140 mmol) and N-methylmorpholine (0.050 ml, 0.454 mmol) inDCM (5 ml) was stirred at room temperature for 10 minutes, after whichTBTU (0.075 g, 0.234 mmol) was added. After 18 hours, the conversion tothe ester (m/z: 766.5) was complete and TFA (1.5 ml) was added to thereaction mixture. After 24 hours the solvent was removed under reducedpressure and the residue was purified by preparative BPLC, using agradient of 30-50% MeCN in 0.1M ammonium acetate buffer as eluent. Thefractions were freeze-dried and the title compound was obtained as awhite solid (0.052 g; 69%). N (CD₃OD, 400 MHz) 2.85-3.00 (m, 4H),3.65-3.85 (m, 2H), 4.00-4.05 (m, 1H), 4.35-4.40 (m, 1H), 4.60 (ABq, 2H),4.85 (d, 1H), 5.65 (s, 1H), 6.95-7.45 (m, 19H); m/z: 654.2.

Example 183-(R)-4-(R)-1-(Phenyl)-3-(phenylethylsulphanyl)-4-{4-[N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]phenyl}azetidin-2-one

A solution of3-(R)4-(R)-1-(phenyl)-3-(phenylethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 9; 0.050 g, 0.110 mmol),(R)-α-{N-[(S)-1-(t-butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamine(Method 11 of WO 03/022286; 30 0.048 g, 0.139 mmol) andN-methylmorpholine (0.051 ml, 0.463 mmol) in DCM (5 ml) was stirred atroom temperature for 10 minutes, after which TBTU (0.075 g, 0.234 mmol)was added. After 20 hours, the conversion to the ester (m/z: 724.4) wascompleted and the solvent was removed under reduced pressure. Theresidue was dissolved in formic acid (3 ml) and the solution was stirredfor 24 hours. The solvent was removed under reduced pressure and theresidue was purified by preparative HPLC using a gradient of 30-50% MeCNin 0.1M ammonium acetate buffer as eluent. The fractions werefreeze-dried and the title compound was obtained as a white solid (0.037g; 48%). M/z: 668.1. NMR (CD₃OD, 400 MHz) 0.65-0.80 (m, 3H), 1.50-1.70(m, 1H), 1.75-1.90 (m, 1H), 2.85-3.00 (m, 4H), 4.00-4.05 (m, 1H),4.20-4.30 (m, 1H), 4.55 (ABq, 2H), 4.85 (d, 1H), 4.45-4.55 (m, 1H),6.65-6.75 (m, 2H), 6.95-7.40 (m, 16H).

Example 193-(R)-4-(R)-1-(Phenyl)-3-(phenylethylsulphanyl)-4-{4-[N-{(R)-α-[N-((S-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]phenyl}azetidin-2-one

To a solution of3-(R)-4-(R)-1-(phenyl)-3-(phenylethylsulphanyl)-4-{4-[N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]phenyl}azetidin-2-one(Example 18; 0.026 g, 0.039 mmol) in DCM (3 ml) was added a solution ofMCPBA in DCM in portions until the reaction was complete (LC/MS).(Approximately 0.015 g 70-75% m-CPBA was added). The solvent was removedunder reduced pressure and the residue was purified by preparative HPLCusing a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer aseluent After freeze-drying, the title compound was obtained as a whitesolid (0.018 g; 67%). NMR (CD₃OD, 400 MHz) (NB: diastereomeric mixtureat the sulphinyl) 0.65-0.80.(m, 6H), 1.55-1.70 (m, 2H), 1.75-1.90 (m,2H), 2.95-3.35 (m, 7H), 3.75-3.90 (m, 1H), 4.20-4.30 (m, 2H), 4.40-4.50(m, 1H), 4.50-4.65 (m, 5H), 5.30 (d, 1H), 5.45-5.55 (m, 2H), 5.65 (d,1H), 6.65-6.80 (m, 4H), 6.95-7.10 (m, 6H), 7.15-7.35 (m, 22H), 7.35-7.50(m, 4H); m/z: 684.4.

Example 203-(R)-4-(R)-1-(Phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 10; 0.110 g, 0.236 mmol), tert-butyl glycinate hydrochloride(0.067 g, 0.400 mmol) and N-methylmorpholine (0.12 ml, 1.09 mmol) in DCM(5 ml) was stirred at room temperature for 5 minutes, after which TBTU(0.130 g, 0.4049 mmol) was added. After 66 hours the conversion to theester (m/z: 579.2) was complete and the solvent was removed underreduced pressure. The residue was dissolved in formic acid (3 ml) andthe solution was stirred at 40° C. for 4 hours. The solvent was removedunder reduced pressure and the residue was purified by preparative HPLCusing a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer aseluent. A white solid was obtained after freeze-drying (0.035 g; 28%).M/z 521.12 [M−1]⁻.

Example 213-(R)-4-(R)-1-(Phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(N-{N-[(R)-1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoylmethyl}carbamoylmethoxy)phenyl]azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one(Example 20; 0.020 g, 0.038 mmol), tert-butyl O-(tert-butyl)-D-serinatehydrochloride (0.012 g, 0.047 mmol) and N-methylmorpholine (0.013 ml,0.118 mmol) in DCM (3 ml) was stirred at room temperature for 10minutes, after which TBTU (0.016 g, 0.050 mmol) was added. After 66hours the solvent was removed under reduced pressure and the residue waspurified by flash chromatography using heptane:EtOAc (1:2) as eluent togive the title compound (0.020 g; 74%). NMR (400 MHz) 1.15 (s, 9H), 1.45(s, 9H), 3.50-3.55 (m, 1H), 3.75-3.85 (m, 1H), 4.00-4.25 (m, 5H), 4.50(s, 2H), 4.55-4.65 (m, 1H), 4.85 (d, 1H), 6.90-7.00 (m, 2H), 7.00-7.40(m, 9H), 7.90-8.05 (m, 2H); m/z: 722.1.

Example 223-(R)-4-(R)-1-(Phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(N-{N-[(R)-1-(carboxy)-2-(hydroxy)ethyl]carbamoylmethyl}carbamoylmethoxy)phenyl]azetidin-2-one

To a solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(N-{N-[(R)-1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoylmethyl}carbamoylmethoxy)phenyl)azetidin-2-one (Example 21; 0.020 g, 0.146 mmol) in DCM (4 ml)was added TFA (1.5 ml). After 18 hours the solvent was removed underreduced pressure and the residue was purified by preparative BPLC usinga gradient of 20-50% MeCN in 0.1M ammonium acetate buffer, as eluent.After freeze-drying, the title compound was obtained as a white solid(0.017 g; ˜quantitative). NMR (CD₃COOH, 400 MHz) δ 3.95 (dd, 1H), 4.10(dd, 1H), 4.15-4.35 (m, 5H), 4.65 (s, 2H), 4.70-4.80 (m, 1H), 5.05 (d,1H), 6.90-7.45 (m, 11H), 7.95-8.10 (m, 2H); m/z: 610.2.

Example 233-(R)-4-(R)-1-(Phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-(4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 10; 0.015 g, 0.032 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate (Method 6;0.017 g, 0.049 mmol) and N-methylmorpholine (0.011 ml, 0.100 mmol) inDCM (3 ml) was stirred at room temperature for 10 minutes, after whichTBTU (0.016 g, 0.50 mmol) was added. After 19 hours the conversion tothe ester (m/z: 798.80) was complete and TFA (1.5 ml)was added to thesolution. After 7 hours the solvent was removed under reduced pressureand the residue was purified by preparative HPLC using a gradient of20-50% MeCN in 0.1M ammonium acetate buffer as eluent. Afterfreeze-drying the title compound was obtained as a white solid (0.016 g;72%). NMR (CD₃COOH, 400 MHz) 3.85 (dd, 1H), 4.05 (dd, 1H), 4.20-4.30 (m,3H), 4.60-4.80 (m, 3H), 5.00 (d, 1H), 5.90-6.00 (m, 1H), 6.90-7.50 (m,16H), 8.00-8.10 (m, 2H); m/z: 686.6.

Example 243-(R)-4-(R)-1-(Phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphany[-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one

To a stirring solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-oneTo a stirring solution of3-(R)-4-(R)-1-(phenyl)-3-(fluorobenzomethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxyphenyl}azetidin-2-one(Example 20; 0.010 g, 0.019 mmol) in MeOH (1 ml) was added sodiumborohydride (0.001 g, 0.026 mmol). After 10 minutes water (1 ml) wasadded and the solvent was removed under reduced pressure. The residuewas purified by preparative HPLC using a gradient of 20-50% MeCN in 0.1Mammonium acetate buffer as eluent. After freeze-drying the titlecompound was obtained as a white solid (0.008 g; 80%). M/z: 525.1. NMR(CD₃COOD, 400 MHz) 3.00-3.20 (m, 2H), 4.05-4.15 (m, 1H), 4.20 (s, 2H),4.70 (s, 2H), 4.85-5.00 (m, 2H), 6.95-7.10 (m, 5H), 7.20-7.45 (m, 8H).

Example 253-(R)-4-(R)-1-(Phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-[4-(N-{N-[(R)-1-(carboxy)-2-(hydroxy)ethyl]carbamoylmethyl}carbamoylmethoxy)phenyl]azetidin-2-one

To a stirred solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(N-{N-[(R)-1-(carboxy)-2-(hydroxy)ethyl]carbamoylmethyl}carbamoylmethoxy)phenyl]azetidin-2-one (Example 22; 0.015 g, 0.025 mmol) in MeOH (2 ml)was added sodium borohydride (0.003 g, 0.079 mmol). After 5 minuteswater (1 ml) was added and the solvent was removed under reducedpressure. The residue was purified by preparative HPLC using a gradientof 20-40% MeCN in 0.1M ammonium acetate buffer as eluent. Afterfreeze-drying the title compound was obtained as a white solid (0.010 g;66%). NMR (CD₃COOD, 400 MHz) 2.95-3.20 (m, 2H), 3.95 (dd, 1H), 4.05-4.15(m, 2H), 4.25 (ABq, 2H), 4.70 (s, 2H), 4.70-4.80 (m, 1H), 4.85-5.00 (m,2H), 6.95-7.10 (m, 5H), 7.20-7.45 (m, 8H).

Example 263-(R)-4-(R)-1-(Phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-((R)-α-{N-](S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

To a solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one(Example 23; 0.019 g, 0.028 mmol) in MeOH (3 ml) was added sodiumborohydride (0.005 g, 0.073 mmol). After 10 minutes 0.1M ammoniumacetate buffer was added (aq, 1 ml) and the solvent was removed underreduced pressure. The residue was purified by preparative HPLC using agradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. Afterfreeze-drying, the title compound was obtained as a white solid (0.008g; 81%). NMR (CD₃COOD, 400 MHz) 3.00-3.20 (m, 2H), 3.85 (dd, 1H),4.00-4.15 (m, 2H), 4.65-4.80 (m, 3H), 4.85-5.00 (m, 2H), 5.95 (s 1H),6.95-7.10 (m, 5H), 7.20-7.50 (m, 13H); m/z 688.21.

Example 273-(R)-4-(R)-1-(Phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of3-(R)-4)-(R)-1-(phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 11; 0.039 g, <0.086 mmol), tert-butyl glycinate hydrochloride(0.020 g, 0.119 mmol) and N-methylmorpholine (0.035 ml, 0.318 mmol) inDCM (3 ml) was stirred at room temperature for 10 minutes, after whichTBTU (0.042 g, 0.131 mmol) was added. After 22 hours the solvent wasremoved under reduced pressure and the residue was purified by flashchromatography using heptane:EtOAc (1:1) as eluent. This gave 0.035 g ofa colourless oil (m/z: 567.1). This oil was dissolved in formic acid (3ml) and the solution was stirred at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammoniumacetate buffer as eluent. After freeze-drying, the title compound wasobtained as a white solid (0.019 g; 43%). NMR (CD₃COOD, 400 MHz) 4.15(ABq, 2H), 4.20 (s, 2H), 4.25 (d, 1H), 4.70 (s, 2H), 5.05 (d, 1H),6.95-7.15 (m, 4H), 7.20-7.30 (m, 4H), 7.35-7.45 (m, 2H), 7.75-7.90 (m,2H); m/z: 511.0.

Example 283-(R)-4-(R)-1-(Phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one (Method 11; 0.039 g, <0.086 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate (Method 6;0.042g) and N-methylmorpholine (0.022 ml) in DCM (4 ml) was stirred atroom temperature for 10 minutes, after which TBTU (0.042 g) was added.After 22 hours the solvent was removed under reduced pressure and theresidue was purified by flash chromatography using heptane:EtOAc (1:1)as eluent to give a colourless oil (0.050 g). M/z: 786.6. This oil wasdissolved in DCM (4 ml) and TFA (1.5 ml) was added. After 19 hours, thesolvent was removed under reduced pressure and the residue was purifiedtwice by preparative HPLC using a gradient of 20-50% MeCN in 0. 1Mammonium acetate buffer as eluent. After freeze-drying, the titlecompound was obtained as a white solid (0.019 g; 33%). No (CD₃COOD, 400MHz) 3.85 (dd, 1H), 4.05 (dd, 1H), 4.15 (ABq, 2H), 4.20-4.30 (m, 1H),4.60-4.75. (m, 3H), 5.05 (d, 1H), 5.90 (s, 1H), 6.95-7.15 (m, 4H),7.20-7.50 (m, 11H), 7.75-7.85 (m, 2H); m/z: 674.3.

Example 293-(R)-4-(R)-1-(Phenyl)-3-[2-(thien-3-yl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one

To a solution of3-(R)-4-(R)-1-(phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one (Example 27; 0.012 g, 0.024 mmol)in MeOH (3 ml) was added sodium borohydride (0.006 g, 0.159 mmol). After10 minutes 0. 1M ammonium acetate buffer (aq, 1 ml) was added and thesolvent was removed under reduced pressure. The residue was purified bypreparative HPLC using a gradient of 20-50% MeCN in 0. 1M ammoniumacetate buffer as eluent. After freeze-drying the title compound wasobtained as a white solid (0.010 g; 80%). NMR (CD₃COOD, 400 MHz) δ3.10-3.30 (m, 2H), 4.15 (dd, 1H), 4.20 (s, 2H), 4.70 (s, 2H), 4.95 (dd,1H), 5.20 (dt, 1H), 6.90-7.10 (m, 5H), 7.20-7.35 (m, 5H), 7.40-7.45 (m,2H); m/z: 511.3 (M−1)⁻.

Example 303-(R)-4-(R)-1-(Phenyl)-3-[2-(thien-3-yl)-2-hydroxyethylsulphanyl]-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

To a solution of3-(R)-4-(R)-1-(phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-{4-[N-(α-(R)-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one(Example 28; 0.019 g, 0.028 mmol) in MeOH (3 ml) was added sodiumborohydride (0.005 g, 0.132 mmol). After 10 minutes 0.1M ammoniumacetate buffer (aq, 1 ml) was added and the solvent was removed underreduced pressure. The residue was purified by preparative HPLC using agradient of 20-50% MeCN in 0. 1M ammonium acetate buffer as eluent.After freeze-drying, the title compound was obtained as a white solid(0.015 g; 79%). NMR (CD₃COOD, 400 MHz) 3.05-3.30 (m, 2H), 3.85 (dd, 1H),4.05 (dd, 1H), 4.15 (dd, 1H), 4.65-4.75 (m, 3H), 4.90 (dd, 1H),5.15-5.25 (m, 1H), 5.95 (s, 1H), 6.90-7.10 (m, 5H), 7.20-7.50 (m, 12H);m/z 674.16 (m−H)⁻.

Example 311-(4-Fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one(Method 17; 0.100 g, 0.213 mmol), tert-butylN-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate (Method 6;0.150 g, 0.428 mmol) and N-methylmorpholine (0.070 ml, 0.635 mmol) inDCM (4 ml) was stirred at room temperature for 10 minutes, after whichTBTU (0.140 g, 0.436 mmol) was added. After 19 hours the solvent wasremoved under reduced pressure and the residue was purified by flashchromatography using heptane:EtOAc (2:1) as eluent to give a colourlessoil (0.149 g; 87%). NMR (400 MHz) 0.90 (s, 9H), 1.45 (s, 9H), 2.05-2.30(m, 2H), 2.95-3.15 (m, 2H), 3.20-3.25 (m, 1H), 3.30-3.35 (m, 1H), 3.65(dd, 1H), 4.40-4.60 (m, 3H ), 4.60 (d, 1H), 5.50 (dd, 1H), 6.50 (dd,1H), 6.85-7.00 (m, 6H), 7.15-7.40 (m, 11H), 7.90 (dd, 1H); m/z: 802.8.

Example 321-(4-Fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

To a solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(t-butoxycarbonyl)-2-(t-butoxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl)azetidin-2-one(Example 31; 0.149 g, 0.186 mmol) in DCM (3 ml) was added TFA (1.5 ml).After 20 hours, the solvent was removed under reduced pressure and theresidue was purified by preparative HPLC using a gradient of 20-50% MeCNin 0.1M ammonium acetate buffer, as eluent. After freeze-drying, thetitle compound was obtained as a white solid (0.098 g; 77%). NMR (400MHz) 2.00-2.25 (m, 2H), 2.85-3.10 (m, 2H), 3.10-3.20 (m, 1H), 3.35-3.45(m, 1H), 3.75-3.85 (m, 1H), 4.15-4.45 (m, 3H), 4.55 (d, 1H), 5.70 (d,1H), 6.70-7.00 (m, 6H), 7.10-7.35 (m, 11H), 7.45-7.55 (m, 1H), 8.45-8.55(m, 1H); m/z: 690.5.

Example 331-(4-Fluorophenyl)-3-[2-(4-fluorophenylsulphinyl)ethyl]-4-{4-[N-((R)-α-55N-(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-oneExample 341-(4-Fluorophenyl)-3-[2-(4-fluorophenylsulphonyl)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one

To a stirring suspension of1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one (Example 32; 0.070 g, 0.102 mmol) in DCM (5 ml) wasadded meta-chloroperoxybenzoic acid (0.035 g, 70-75%). After 20 hours,the solvent was removed under reduced pressure and the residue waspurified by preparative HPLC using a gradient of 20-40% MeCN in 0.1Mammonium acetate buffer as eluent. After freeze-drying,1-(4-fluorophenyl)-3-[2-(4-fluorophenylsulphinyl)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one(0.022 g; 30%) NMR (CD₃COOD, 400 MHz) 2.15-2.45 (m, 2H), 3.10-3.35 (m,3H), 3.85 (dd, 1H), 4.05 (dd, 1H), 4.65-4.75 (m, 3H), 4.80-4.90 (m, 1H),5.90 (s, 1H), 6.95-7.05 (m. 4H), 7.25-7.50 (m, 11H), 7.70-7.80 (m, 2H);m/z: 706.2; and 1-(4-fluorophenyl)-3-[2-(4-fluorophenylsulphonyl)ethyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one (0.043 g; 59%) NM (CD₃COOD, 400MHz) 2.25-2.40 (m, 2H), 3.25 (dt, 1H), 3.35-3.55 (m, 2H), 3.85 (dd, 1H),4.05 (dd, 1H), 4.65-4.75 (m, 3H), 4.85 (d, 1H), 5.95 (s, 1H), 6.95-7.05(m, 4H), 7.20-7.50 (m, 11H), 7.95-8.05 (m, 2H); m/z: 722.1 were obtainedas a white solids.

Example 351-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-α-(carboxy)benzyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2, 49 mg, 0.105 mmol) was dissolved in a solution ofN-methylmorpholine (35 μl, 0.318 mmol) in 2 ml DCM. (S)-Phenylglycinemethyl ester hydrochloride (25 mg, 0.124 mmol) and TBTU (40 mg, 0.125mmol) were added and the mixture was stirred at ambient temperature overnight. The solution was diluted with 4 ml DCM and washed with 1% NaHCO₃,0.1M KHSO₄ and brine. The organic phase was dried and evaporated to givethe ester. M/z: 615. THF (2 ml), water (0.5 ml) and LiOH (ca 10 mg,0.418 mmol) were added and the mixture was stirred over night. Thesolvent was removed and the residue was purified using preparative HPLCon a C8-column. A gradient from 20 to 50% MeCN in 0.1M ammonium acetatebuffer was used as the mobile phase. Lyophilisation yielded a whitesolid. Mass: 40 mg (63%). M/z: 601. NMR (400 MHz, CD₃OD): 1.75-2.06 (m,4H), 3.06-3.13 (m, 1H), 4.47-4.67 (m, 3H), 4.79-4.82 (m, 1H), 5.24 (d,1H), 6.90-7.06 (m, 6H), 7.12-7.40 (m, 11H).

Example 361-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)phenyl]azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one (Method 2; 49 mg, 0.105 mmol) was dissolved in a solutionof N-methylmorpholine (40 μl, 0.318 mmol) in 2 ml DCM. tert-Butyl(2S)-2-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}butanoatehydrochloride (Method 14,43 mg, 0.125 mmol) and TBTU (40 mg, 0.125 mmol)were added. The mixture was stirred over night at ambient temperature.Additionally 10 mg (0.029 mmol) of the dipeptide was added and after 2hours the solution was diluted with 4 ml DCM and washed with 1%NaHCO₃,0.0M KHSO₄ and brine. The organic phase was dried and evaporated to givethe ester. M/z: 758. Formic acid (1.5 ml) was added and the mixture wasstirred over night. Additionally 1 ml formic acid was added. After 3hours the formic acid was removed and MeOH (2 ml) together with Et₃N (40μl, 0.288 mmol) were added and the mixture was stirred over night. Themixture was concentrated under reduced pressure and purified usingpreparative chromatography. A gradient from 20% to 80% MeCN in 0.1Mammonium acetate buffer was used as eluent. Lyophilisation yielded 42 mg(57%). NMR (400 MHz, DMSO-d₆): 0.65-0.72 (m, 3H), 1.53-1.67 (m, 1H),1.74-2.04 (m, 5H), 3.06-3.14 (m, 1H), 4.18-4.23 (m, 1H), 4.50-4.66 (m,3H), 4.77-4.82 (m, 1H), 5.46 (d, 1H), 6.72 (t, 2H), 6.93-7.06 (m, 6H),7.18-7.36 (m, 8H); m/z: 702.

Example 371-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-hydroxyethyl)carbamoylmethoxy]phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2, 20 mg, 0.043 mmol) was dissolved in a solution ofN-methylmorpholine (10 μl, 0.091 mmol) in 2 ml DCM. 2-Aminoethanol (4μl, 0.066 mmol) and TBTU (16 mg, 0.050 mmol) were added and the mixturewas stirred for 3 hours. Additional 2-aminoethanol (3 μl) was added. Themixture was stirred for 2.5 days then concentrated and purified usingpreparative chromatography. A gradient from 20% to 50% MeCN in 0.1Mammonium acetate buffer was used as eluent. Lyophilisation yielded 10 mg(45%). NMR (400 MHz, CD₃OD): 1.75-2.06 (m, 4H), 3.05-3.12 (m, 1H), 3.38(t, 2H), 3.61 (t, 2H), 4.51 (d, 2H), 4.574.66 (m, 1H), 4.774.83 (m, 1H),6.93-7.07 (m, 6H), 7.22-7.37 (m, 6H); m/z: 511.

Example 381-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-methoxyethyl)carbamoylmethoxy]phenyl }azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2, 20 mg, 0.043 mmol) was dissolved in a solution ofN-methylmorpholine (10 μl, 0.091 mmol) in 2 ml DCM. 2-Methoxyethylamine(5 μl, 0.058 mmol) and TBTU (16 mg, 0.050 mmol) were added and themixture was stirred for 3 hours at ambient temperature. The mixture wasconcentrated and purified using preparative chromatography. A gradientfrom 20% to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent.Lyophilisation yielded 5 mg (22%). NMR (400 MHz, CD₃OD): 1.75-2.05 (m,4H), 3.05-3.15 (m, 1H), 3.29 (s, 3H), 3.40-3.44 (m, 4H), 4.5 (d, 2H),4.57-4.66 (m, 1H), 4.78-4.82 (m, 1H), 6.92-7.06 (m, 6H), 7.22-7.37 (m,6H); m/z: 525.

Example 391-(4-Fluorolphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-sulphoethyl)carbamoylmethoxy]phenyl}azetidin-2-one

TBTU (26 mg, 0.081 mmol) was added to a mixture of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 29 mg, 0.062 mmol), taurine (24 mg, 0.19 mmol) andtriethylamine (25 mg, 0.25 mmol) in MeCN (1 ml). After 1 hour DMF (1 ml)was added and the MeCN was removed in vacuo at 50° C. After 4 days atroom temperature the mixture was purified by preparative HPLC using agradient of MeCN/ammonium acetate buffer to give the title compound (2mg, 6%). NMR (CD₃OD, 400 MHz) 7.40-7.20 (m, 6H), 7.05-6.95 (m, 6H), 4.8(m, 1H), 4.7-4.55 (m, 1H), 4.5 (s, 2H), 3.75 (t, 2H), 3.1 (m, 1H), 2.95(t, 2H), 2.0-1.8 (m, 4H).

Example 401-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 30 mg, 0.064 mmol), tert-butyl L-alaninate hydrochloride (40mg, 0.22 mmol), triethyl amine (0.036 ml, 0.26 mmol) and TBTU (35 mg,0.11 mmol) were mixed (in that order) in MeCN (1 ml). After 4 hours themixture was diluted with toluene and the solution was washed withhydrochloric acid (2M) and sodium hydrogen carbonate solution. Thesolvent was removed in vacuo and the residue was purified by preparativeHPLC using a gradient of MeCN/ammonium acetate buffer to give the titlecompound (20 mg, 52%). N (CD₃OD, 500 MHz) 7.40-6.90 (m), 4.8 (m),4.7-4.3 (m), 3.95 (q), 3.2 (q), 3.1 (m), 2-1.8 (m), 1.5-1.3 (m); m/z595.60 (M+H)⁺ and 593.53 (M−H)⁻.

Example 411-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1-(carboxy)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{(N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one(Example 40; 20 mg, 0.034 mmol) in formic acid (1 ml) was kept at roomtemperature overnight. The formic acid was removed in vacuo and theresidue was dissolved in methanol (4 ml). Aqueous ammonia (25%, 0.2 ml)was added and after 1 hour at room temperature the mixture was purifiedby preparative HPLC using a gradient of MeCN/ammonium acetate buffer togive the title compound (5 mg, 28%). NMR (CD₃OD, 400 MHz) 7.4-7.2 (m,6H), 7.1-6.9 (m, 6H), 4,8 (m, 1H), 4.7-4.6 (m, 1H), 4.5 (s, 2H), 4.3 (q,1H), 3.1 (m, 1H), 2-1.7 (m, 4H), 1.4 (dd, 3H); m/z 539.51 (M⁺H)⁺ and537.50 (M−H)⁻.

Example 421-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)phenyl]azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 28 mg, 0.06 mmol),2-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}ethanesulfon acid (30mg, 0.11 mmol), triethylamine (24 mg, 0.24 mmol), and TBTU (29 mg, 0.09mmol) were mixed in DMF (1.5 ml). After stirring overnight the reactionmixture was purified by preparative IPLC using a gradient ofMeCN/ammonium acetate buffer to give the title compound (18 mg, 42%).NMR (CD₃OD, 400 MHz) 7.4-7.1 (m), 7.1-6.9 (m), 5.4 (m), 4.8 (m), 4.7-4.5(m), 3.65-3.55 (m), 3.15-3.05 (m), 3-2.8 (m), 2-1.7 (m); m/z 724.46(M+H)⁺ and 722.54 (M−H)⁻.

Example 431-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((S)-1-{N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoyl}ethyl)carbamoylmethoxy]phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 30 mg, 0.064 mmol), tert-butyl L-alanyl-L-alaninate (25 mg,0.12 mmol), triethylamine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.10mmol) were mixed (in that order) in DMF (1.5 ml). After 16 hours themixture was diluted with toluene and the solution was washed with water,hydrochloric acid (2M), water and sodium hydrogen carbonate solution andwater. Addition of IPA and removal of the solvents in vacuo gave thetitle compound. M/z 666.57 (M+H)⁺ and 664.68 (M−H)⁻.

Example 441-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((S)-1-{N-[(S)-1-(carboxy)ethyl]carbamoyl}ethyl)carbamoylmethoxy]phenyl}azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((S)-1-{N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoyl}ethyl)carbamoylmethoxy]phenyl}azetidin-2-one(Example 43; 54 mg, 0.081 mmol) was dissolved in formic acid (2 ml).After 16 hours the formic acid was removed in vacuo and the residue wasdissolved in methanol (4 ml) and aqueous ammonia (25%, 0.2 ml). After 6hours the mixture was purified by preparative HPLC using a gradient ofMeCN/ammonium acetate buffer to give the title compound (15 mg, 30%).NMR (CD₃OD, 400 MHz) 7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H),4.7-4.5 (m, 1H), 4.5 (s, 2H), 4.45 (q, 1H), 4.3-4.2 (m, 1H), 3.2 (q,1H), 3.1-3.0 (m, 1H), 2-1.8 (m, 4H), 1.4-1.2 (dd, 6H); m/z 610.57 (M⁺H)⁺and 608.53 (m−H)⁻.

Example 451-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[N-(methoxycarbonylmethyl)carbamoylmethyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 30 mg, 0.064 mmol), methyl glycylglycinate (19 mg, 0.13mmol), triethyl amine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.10 mmol)were mixed (in that order) in DMF (1.5 ml). After 16 hours the mixturewas diluted with toluene and the solution was washed with water,hydrochloric acid (2M), water and sodium hydrogen carbonate solution andwater. Addition of IPA and removal of the solvents in vacuo gave thetitle compound. M/z 596.50 (M+H)⁺ and 594.45 (M−H)⁻.

Example 461-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[N-(carboxymethyl)carbamoylmethyl]carbamoylmethoxy}phenyl)azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[N-(methoxycarbonylmethyl)carbamoylmethyl]carbamoylmethoxy}phenyl)azetidin-2-one(Example 45; 44 mg, 0.074 mmol) in THF (4 ml) was added to a stirredsolution of lithium hydroxide (10 mg, 0.43 mmol) in water (2 ml). After16 hours the mixture was carefully neutralized with hydrochloric acid.Purification by preparative HPLC using a gradient of MeCN/ammoniumacetate buffer gave the title compound (17 mg, 40%). NMR (CD₃OD, 400MHz) 7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.6 (m, 1H), 4.6(s, 2H), 3.95 (s, 2H), 3.8 (s, 2H), 3.1-3.05 (m, 1H), 2-1.8 (m, 4H).

Example 471-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1,3-bis-(ethoxycarbonyl)propyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 30 mg, 0.064 mmol), diethyl L-glutamate (19 mg, 0.093 mmol),triethylamine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.10 mmol) weremixed (in that order) in DMN (1.5 ml). After 16 hours the mixture wasdiluted with toluene and the solution was washed with water,hydrochloric acid (2M), water and sodium hydrogen carbonate solution andwater. Addition of IPA and removal of the solvents in vacuo gave thetitle compound. M/z 653.56 (M+H)⁺ and 651.60 (M−H)⁻.

Example 481-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1,3-bis-(carboxy)propyl]carbamoylmethoxy}phenyl)azetidin-2-one

To a solution of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1,3-bis-(ethoxycarbonyl)propyl]carbanoylmethoxy}phenyl)azetidin-2-one(Example 47; 30 mg, 0.046 mmol) in ethanol (4 ml) was added 3.75 Msodium hydroxide solution (0.05 ml, 0.19 mmol). After 16 hours more3.75M sodium hydroxide solution (0.05 ml, 0.19 mmol) was added. Theethanol was removed in vacuo and THF (2.5 ml) and water (1.5 ml) wereadded. After 24 hours the reaction mixture was purified by preparativeHPLC using a gradient of MeCN/ammonium acetate buffer to give the titlecompound (11 mg, 40%). NMR (CD₃OD, 400 MHz) 7.5-6.9 (m), 5-4.8 (m),4.75-4.6 (m), 4.5 (s), 4.45 (m), 4.4-4-3 (br s), 3.1-3.05 (m), 2.3-2.1(m), 2-1.8 (m); m/z 597.52 (M+H)⁺ and 595.49 (M−H)⁻.

Example 491-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1-(t-butoxycarbonyl)-5-(t-butoxycarbonylamino)pentyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 30 mg, 0.064 mmol), tert-butylN⁶-(tert-butoxycarbonyl)-L-lysinate (39 mg, 0.13 mmol), triethyl amine(0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.096 mmol) were mixed in DMF(1.50 ml). The mixture was stirred for 16 hours and then diluted withwater and toluene. The organic phase was washed with hydrochloric acid,water, sodium bicarbonate solution and then water. IPA was added to theorganic phase and the solvents were removed in vacuo to give the titlecompound (39 mg, 81%). M/z 752.68 (M+H)⁺ and 750.79 (M−H)⁻.

Example 501-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1-(carboxy)-5-(amino)pentyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(S)-1-(t-butoxycarbonyl)-5-(t-butoxycarbonylamino)pentyl]carbamoylmethoxy}phenyl)azetidin-2-one(Example 49; 39 mg, 0.052 mmol) was kept in formic acid (2 ml) for 64hours. The acid was removed in vacuo and the residue was dissolved inmethanol (4 ml) and aqueous ammonia (25%, 0.4 ml). After 16 hours thesolvent was removed in vacuo and the residue was purified by preparativeHPLC using a gradient of MeCN/ammonium acetate buffer to give the titlecompound (7 mg, 23%). NMR (CD₃OD, 400 MHz) 7.4-7.2 (m, 6H), 7.05-6.95(m, 6H), 4.8 (m, 1H), 4.65-4.6 (m, 1H), 4.5 (s, 2H), 4.35-4-3 (m, 1H),3.1-3.05 (m, 1H), 2.9-2.8 (m, 2H), 2-1.6 (m, 6H), 1.5-1.2 (m, 4H).

Example 511-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[2-(t-butoxycarbonyl)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

A mixture of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 47 mg, 0.101 mmol), tert-butyl β-alaninate (48 mg, 0.33mmol), triethylamine (0.07 ml, 0.5 mmol), and TBTU (42 mg, 0.13 mmol)were mixed in DMF (1 ml) and left overnight. The mixture was dilutedwith diethyl ether and washed with potassium hydrogen sulphate solutionand sodium carbonate solution. The organic phase was dried (magnesiumsulphate) and the solvent was removed in vacuo to give the titlecompound (38 mg, 64%). M/z 595.54 (M+H)⁺ and 593.61 (M−H)⁻.

Example 521-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[2-(carboxy)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[2-(t-butoxycarbonyl)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one(Example 51; 38 mg, 0.064 mmol) was dissolved in formic acid (2 ml).After 16 hours the acid was removed in vacuo with the aid of MeCN. Aftercomplete removal of the solvents the residue was dissolved in methanol(5 ml) and aqueous ammonia (25%, 1 ml). Hydrolysis was complete in 2hours and purification by HPLC using a gradient of MeCN/ammonium acetatebuffer gave the title compound (20 mg, 59%). NMR (CD₃OD, 400 MHz)7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.6 (m, 1H), 4.5 (s,2H), 3.5 (t, 2H), 3.1-3.05 (m, 1H), 2.4 (t, 2H), 2-1.8 (m, 4H); m/z539.42 (M+H)⁺ and 537.50 (M−H)⁻.

Example 531-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(R)-1-(t-butoxycarbonyl)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one(Method 2; 30 mg, 0.064 mmol), tert-butyl D-alaninate hydrochloride (50mg, 0.28 mmol), triethylamine (0.05 ml, 0.36 mmol) and TBTU (31 mg,0.096 mmol) were stirred in DMP (1 ml) for 3 hours. The mixture wasdiluted with toluene and washed with water, hydrochloric acid, water,sodium bicarbonate solution and water. IPA was added to the organicphase and the solvents were removed in vacuo to give 30 mg (79%) of thetitle compound. M/z 595.48 (M+H)⁺ and 593.56 (M−H)⁻.

Example 541-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(R)-1-(carboxy)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(R)-14-(t-butoxycarbonyl)ethyl]carbamoylmethoxy}phenyl)azetidin-2-one(Example 54; 30 mg, 0.05 mmol) was dissolved in formic acid (2 ml).After 16 hours the acid was removed in vacuo and the residue wasdissolved in methanol (3 ml) and aqueous ammonia (25%, 0.2 ml). Theprogress was followed by HPLC and after completion the mixture waspurified by HPLC using a gradient of MeCN/ammonium acetate buffer togive the title compound (17 mg, 63%). NMR (CD₃OD, 400 MHz) 7.4-7.2 (m,6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.6 (m, 1H), 4.5 (s, 2H), 4.3-4.2(s, 1H), 3.1-3.05 (m, 1H), 2.2-1.8 (m, 4H), 1.5-1.4 (m, 3H).

Preparation of Starting Materials

The starting materials for the Examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Method 1

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-t-butoxycarbonylmethoxyphenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (J. Med. Chem. 1998, 41, 973-980; 50 mg, 0.122 mmol),tert-butylbromoacetate (24 μl, 0.165 mmol), sodium carbonate (80 mg,0.76 mmol) and a catalytic amount of caesium carbonate were added toMeCN (3 ml) and the mixture was stirred for 1.5 hours at 50° C. Thesolids were filtered off and the solvent was evaporated under reducedpressure. Purification of the residue by column chromatography usingDCM/EtOAc (100/7) as eluent gave 35 mg, (55%) of the title compound. NMR(300 MHz): 1.45 (s, 9H), 1.8-2.1 (m, 4H), 2.25-2.3 (m, 1H), 3.05-3.15(m, 1H), 4.5 (s, 2H), 4.55-4.6 (m, 1H), 4.75 (bs, 1H), 6.9-7.3 (m, 12H);m/z 524.3.

Method 2

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-carboxymethoxyphenyl)azetidin-2-one

1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-t-butoxycarbonylmethoxyphenyl)azetidin-2-one (Method 1; 50 mg, 0.096 mmol) was added toformic acid (3 ml) and the mixture was stirred for 1.5 hours at roomtemperature. The solvent was evaporated under reduced pressure andmethanol (3 ml) and triethylamine (150 μl) were added to the residue.The mixture was stirred for 2 hours at room temperature and the solventswere evaporated under reduced pressure. The residue was purified bypreparative HPLC using MeCN/ammonium acetate buffer (35:65) as eluent.The collected fractions were lyophilised to obtain 32 mg (56%) of thetitle compound. NMR (300 MHz, CD₃OD): 1.8-1.95 (m, 4H), 3.1 (bs, 1H),4.4 (s, 2H), 4.55-4.65 (m, 1H), 4.8 (bs, 1H), 6.9-7.35 (m, 12H); m/z466.1 (M−H)⁻.

Method 3

tert-ButylN-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl)glycinate

(2R)-{[(benzyloxy)carbonyl]amino}(phenyl)acetic acid (Z-(R)-Phg-OH) (10g, 35.0 mmol) and tert-butylglycine hydrochloride (6.3 g, 37.4 mmol) wasdissolved in DCM (200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). Afterstirring 5 minutes at 0° C. TBTU (12.4 g, 38.6 mmol) was added andstirring was continued 1 hours 30 minutes at 0° C. and 3 hours 45minutes at room temperature. The reaction mixture was washed with water(2×100 ml), dried (magnesium sulphate) and purified with flashchromatography (DCM:EtOAc 7:1→5:1) to give the tide compound (13 g,94%). NMR (500 MHz): 1.45 (s, 9 H), 3.84 (d, 1 H), 4.00 (dd, 1 H), 5.10(m, 2 H), 5.28 (br s, 1 H), 6.13 (br s, 1 H), 6.23 (br s, 1 H),7.30-7.44 (m, 10 H).

Method 4

tert-Butyl N-[(2R)-2-amino-2-phenylethanoyl]glycinate

tert-ButylN-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl)glycinate(Method 3; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) andtoluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation wasperformed at atmospheric pressure for 5 hours 30 minutes at roomtemperature. The reaction mixture was filtered through diatomaceousearth and the solvents were evaporated to give the title compound (8.4g, 99%). NMR (600 MHz): 1.45 (s, 9 H), 3.93 (m, 2 H), 4.54 (s, 1 H),7.31-7.42 (m, 5 H), 7.51 (br s, 1 H)

Method 5

tert-ButylN-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl)-O-(tert-butyl)-L-serinate

(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (Z-(R)-Phg-OH) (2.0g, 7.0 mmol) and tert-butyl O-(tert-butyl)-L-serinate (2.0 g, 7.9 mmol)and 2.6-lutidine were dissolved in DCM (30 ml). After stirring 5 minutesat 0° C. TBTU (2.5 g, 7.8 mmol) was added and stirring was continued 30minutes at 0° C. and 4 hours at room temperature. The reaction mixturewas washed with water (2×100 ml), dried and purified with flashchromatography (DCM) to give the title compound (3.3 g, 97%). NMR (300MHz, CD₃OD): 1.05 (s, 9H), 1.45 (s, 9H), 3.4-3.8 (m, 2H), 4.5 (bs, 1H),4.85 (s, 2H), 5.1 (s, 2H), 5.4 (s, 1H), 7.25-7.5 (m, 10 H).

Method 6

tert-Butyl N-[(2R)-2-amino-2-phenylethanoyl]-O-(tert-butyl)-L-serinate

tert-ButylN-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl)-O-(tert-butyl)-L-serinate(Method 5; 3.3 g, 6.8 mmol) was dissolved in EtOH (95%, 30 ml) and a catamount of Pd/C (5%)(50% in water) was added and hydrogenation wasperformed at atmospheric pressure for 3 hours at room temperature. Thereaction mixture was filtered through diatomaceous earth and the solventwas evaporated to give the title compound (2.35 g, 98%). NMR (500 MHz,CD₃OD): 1.1 (s, 9H), 1.45 (s, 9H), 3.45-3.8 (m, 2H), 4.5 (t, 1H), 4.55(s, 1H), 4.85 (s, 2H), 7.3-7.5 (m, 5H).

Method 7

1-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(t-butoxycarbonylmethoxyphenyl]azetidin-2-one

A mixture of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-(4-hydroxyphenyl)azetidin-2-one(Prepared according to Bioorg. Med. Chem. Lett. 1996, 6, 1271-1274; 1.00g, 2.53 mmol), t-butyl bromoacetate (0.42 ml, 2.79 mmol) and caesiumcarbonate (1.00 g, 3.07 mmol) in MeCN (10 ml) was stirred at 40° C. for90 minutes. The suspension was filtered and the solid material waswashed with MeCN (5 ml) and EtOAc (5 ml). The filtrate was concentratedand the residue was purified by flash chromatography using a mixture ofhexane and EtOAc (7:2) as eluent. The title compound was obtained as acolourless oil (1.045 g; 81%). NMR (600 MHz) 1.45 (s, 9H), 2.25-2.45 (m,2H), 3.20-3.30 (m, 1H), 4.00-4-10 (m, 1H), 4.10-4.20 (m, 1H), 4.50 (s,2H), 4.80 (d, 1H), 6.75-7.00 (m, 8H), 5 7.20-7.30 (m, 4H); m/z: 501.2.

Method 8

1-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one(Method 7; 1.045 g, 2.05.1 mmol) in formic acid (4 ml) was stirred atroom temperature for 22 hours. The solvent was removed under reducedpressure and the residue was dissolved in DCM (10 ml). The organic layerwas successively washed with a saturated solution of sodium hydrogencarbonate (aq; 5 ml), water (5 ml) and brine (5 ml), dried andconcentrated to give the title compound as a white solid (0.941 g;˜quantitative yield). NMR (400 MHz) 2.25-2.45 (m, 2H), 3.20-3.30 (m,1H), 4.00-4.20 (m, 2H), 4.65 (s, 2H), 4.80 (d, 1H), 6.75-6.80 (m, 2H),6.85-7.00 (m, 6H), 7.20-7.30 (m, 4H); m/z: 454.0.

Method 9

3-(R)-4-(R)-1-(Phenyl)-3-(phenylethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one

3-(R)-4-(R)-1-(Phenyl)-3-(phenylethylsulphanyl)-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one (Method 15; 220 mg) was stirred in formic acid (2ml) for 20 hours at ambient temperature. The formic acid was thenevaporated. Toluene was added and evaporated twice to give the titlecompound (180 mg). NMR 400 MHz, CD₃OD): 2.86-3.00 (m, 4H), 4.03 (d, 1H),4.66 (s, 2H), 4.87 (d, 1H), 6.93-7.35 (m, 14H).

Method 10

3-(R)-4-(R)-1-(Phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-(4-hydroxyphenyl)azetidin-2-one(synthesized according to WO 96/16037; 0.100 g, 0.245 mmol), caesiumcarbonate (0.040 g, 0.123 mmol) and t-butyl bromoacetate (0.019 ml,0.129 mmol) in MeCN (0.5 ml) was stirred at room temperature for 10minutes, after which more caesium carbonate (0.040 g, 0.123 mmol) andt-butyl bromoacetate (0.019 ml, 0.129 mmol) were added. After 7 hourswater (5 ml) and AcOH (0.05 ml) were added to the reaction mixture andthe organic solvent was removed under reduced pressure. The water layerwas extracted twice with DCM (2×5 ml) and the combined organic layerswere washed with brine, dried over magnesium sulphate and concentrated.The residue was purified twice by flash chromatography usingheptane:EtOAc (3:1) as eluent, which gave a colourless oil (0.066 g).M/z: 522.1. This oil was dissolved in formic acid (3 ml) and thesolution was stirred at room temperature for 18 hours. The solvent wasremoved under reduced pressure and the residue was purified bypreparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammoniumacetate buffer as eluent. The title compound was obtained as a whitesolid (0.025 g; 22%). NMR (CD₃COOD, 400 MHz) 4.20 (d, 1H), 4.25 (s, 2H),4.70 (s, 2H), 5.00 (d, 1H), 6.90-7.10 (m, 2H), 7.00-7.40 (m, 9H),8.00-8.10 (m, 2H); m/z: 465.9.

Method 11

3-(R)-4-(R)-1-(Phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-[4-(carboxymethoxy)phenyl]azetidin-2-one

A solution of3-(R)-4-(R)-1-(phenyl)-3-(thien-3-ylcarbonylmethylsulphanyl)-4-(4-hydroxyphenyl)azetidin-2-one(synthesized according to WO 96/16037; 0.100 g, 0.253 mmol), caesiumcarbonate (0.043 g, 0.132 mmol) and t-butyl bromoacetate (0.019 ml,0.126 mmol) in MeCN (6 ml) was stirred at room temperature for 10minutes, after which more caesium carbonate (0.040 g, 0.123 mmol) andt-butyl bromoacetate (0.019 ml, 0.126 mmol) were added. After 7 hourswater (7 ml) and AcOH (0.05 ml) were added and the solvent was removedunder reduced pressure. The water layer was extracted twice with DCM(2×3 ml) and the combined organic layers were washed with brine, driedover magnesium sulphate and concentrated. The residue was purified byflash chromatography using heptane:EtOAc (3:1) as eluent, which gave0.103 g of a colourless oil (m/z: 510.1). This oil was dissolved informic acid (3 ml) and the solution was stirred for 18 hours at roomtemperature. The solvent was removed under reduced pressure and theresidue was dissolved in DCM. The solution was washed two times withwater and one time with brine, dried over magnesium sulphate andconcentrated. This gave a colourless oil which was used without furtherpurification (0.079 g). M/z: 453.9.

Method 12

1-(4-Fluorophenyl)-3-(2-chloroethyl)-4-(4-hydroxyphenyl)azetidin-2-one

A stirring mixture of1-(4-fluorophenyl)-3-(2-chloroethyl)-4-[4-(benzyloxy)phenyl]azetidin-2-one(prepared according to Bioorg. Med. Chem. Lett. 1996, 6, 1271-1274; 2.00g, 4.88 mmol), Pd(OH)₂/C (0.500 g, 20%) and cyclohexene (6 ml) in MeOH(60 ml) was heated to 70° C. After 2 hours, the reaction mixture wascooled to room temperature and was filtered through diatomaceous earth.The solvent was removed under reduced pressure to give the titlecompound (1.57 g; -quantitative yield). No further purification wasnecessary. NMR (CD₃OD, 400 MHz) 2.20-2.40 (m, 2H), 3.20-3.40 (m, 1H),3.70 (t, 2H), 4.85 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.00 (m, 2H),7.15-7.30 (m, 4H); m/z: 320.0.

Method 13

1-(4-Fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-(4-hydroxyphenyl)azetidin-2-one

To a stirring solution of1-(4-fluorophenyl)-3-(2-chloroethyl)-4-(4-hydroxyphenyl)azetidin-2-one(Method 12; 0.750 g, 2.35 mmol) in MeCN (10 ml) was added4-fluorothiophenol (0.500 ml, 4.60 mmol) and triethylamine (0.500 ml,3.59 mmol) at room temperature. After 20 hours there were still startmateriel left (approximately 20%, LC/MS) and more 4-fluorothiophenol(0.250 ml, 2.30 mmol) and triethylamine (0.170 ml, 1.22 mmol) wereadded. After 24 hours, the solvent was removed under reduced pressureand the residue was partitioned between water (20 ml) and EtOAc (20 ml).The organic layer was washed with brine (5 ml), dried over magnesiumsulphate and concentrated. The residue was refluxed in heptane for 30minutes before the title compound was filtered off as a grey solid(0.946 g; 98%). NMR (CD₃OD, 400 MHz) 2.00-2.20 (m, 2H), 3.05 (t, 2H),3.25 (dt, 1H), 4.75 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.05 (m, 4H),7.15-7.40 (m, 6H); m/z: 412.0.

Method 14

tert-Butyl(2S)-2-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}butanoatehydrochloride

tert-butyl(2S)-2-{[(2R)-2-{[(benzyloxy)carbonyl]amino}-2-(4-hydroxyphenyl)acetyl]amino}butanoate(Method 18, 47 g, 106.2 mmol) was dissolved in 400 ml 95.5% ethanol.Pd/C (5%, 3.0 g) was added and the mixture was hydrogenated under H₂(g)at 1 bar pressure at ambient temperature. The hydrogenation wasterminated after 20 hours and the catalyst was filtered off on SiO₂ andwashed with ethanol. The filtrate was concentrated and the residue (ca35 g) was dissolved in 300 ml MeCN. Pyridine hydrochloride (14 g) wasadded and the mixture was left to crystallize for 2.5 days. The formedsalt was filtered off and washed with 2×50 ml MeCN. The solid was driedunder vacuum at 40° C. to yield 29.6 g (81%) of a white crystallineproduct. NMR (300 MHz, DMSO-d₆): 0.64 (t, 3H), 1.39 (s, 9H), 1.40-1.70(m, 2H), 3.98-4.04 (m, 1H), 4.90 (brs, 1H), 6.78 (d, 2H), 7.32 (d, 2H),8.63 (brs, 3H), 8.79 (d, 1H), 9.83 (brs, 1H).

Method 15

3-(R)-4-(R)-1-(Phenyl)-3-(phenylethylsulphanyl)-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one

A mixture of3-R)-4-(R)-1-(phenyl)-3-(phenylethylsulphanyl)-4-(4-hydroxyphenyl)azetidin-2-one(synthesized according to WO 96/16037; 0.5 g, 1,33 mmol), t-butylbromoacetate (0.31 g, 1.58 mmol), sodium carbonate (0.56 g, 5.28 mmol)and cesium carbonate (0.12 g, 0.36 mmol) in MeCN was stirred at 50° C.overnight. The reaction mixture was filtered and the solvent was removedunder reduced pressure. The residue was purified by chromatography(EtOAc:isohexane, 1:6) to give the title compound 220 mg (33%). M/z490.1.

Method 16

1-(4-Fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one

A suspension of1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-(4-hydroxyphenyl)azetidin-2-one(Method 13; 0.800 g, 1.944 mmol), t-butyl bromoacetate (0.32 ml, 2.17mmol) and caesium carbonate (0.700 g, 2.15 mmol) in MeCN (15 ml) wasstirred at room temperature for 2 hours. The solvent was removed underreduced pressure and the residue was partitioned between water (20 ml)and DCM (20 ml). The water layer was extracted once more with DCM (10ml) and the combined organic layers were washed with brine, dried overmagnesium sulphate and concentrated. The residue was purified by flashchromatography using heptane:EtOAc (4:1) as eluent The title compoundwas obtained as a colourless oil (0.884 g; 87%). NMR (400 MHz) 1.45 (s,9H), 2.00-2.30 (m, 2H), 2.90-3.10 (m, 2H), 3.15-3.25 (m, 1H), 4.50 (s,2H), 4.60 (d, 1H), 6.85-7.00 (m, 6H), 7.15-7.35 (m, 6H); m/z: 526.2.

Method 17

1-(4-Fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-[4-(carboxymethoxy)phenyl]azetidin-2-one

A solution of1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one(Method 16; 0.880 g, 1.67 mmol) in formic acid (5 ml) was stirred atroom temperature for 19 hours. The solvent was removed under reducedpressure and the residue was dissolved in DCM (25 ml). The organic layerwas washed twice with water (1×10 ml and 1×5 ml) and once with brine (5ml), dried over magnesium sulphate and concentrated. This gave the titlecompound as a colourless oil (0.800 g; ˜quantitative yield). NMR(CD₃COOD, 400 MHz) 2.10-2.30 (m, 2H), 3.10 (dt, 2H), 3.30-3.40 (m, 1H),4.75 (s, 2H), 4.80 (d, 1H), 6.95-7.05 (m, 6H), 7.25-7.40 (m, 6H); m/z:470.2.

Method 18

tert-Butyl(2S)-2-{[(2R)-2-{[(benzyloxy)carbonyl]amino}-2-(4-hydroxyphenyl)acetyl]amino}butanoate

(R)-N-Benzyloxycarbonyl-4-hydroxyphenylglycine (J. Chem. Soc. PerkinTrans. 1, EN, 7, 1991, 1629-1635; 24.9 g, 82.6 mmol), (S)-2-aminobutyricacid t-butyl ester hydrochloride (18.6 g, 95.0 mmol) andN-methylmorpholine (23.0 g, 227.4 mmol) were dissolved in 220 ml DMF.TBTU (33.7 g, 105.0 mmol) was added in portions over 10 min. Thereaction mixture was stirred for 1 hour at ambient temperature.Approximately 100 ml solvent was evaporated from the solution. Water(250 ml) was added to the remaining solution, which caused the productto precipitate. The mixture was left overnight then the solid wasfiltered off and washed with 30% methanol (200 ml) and hexane (100 ml).The solid was dispersed in 100 ml t-butyl methyl ether and stirred for 1hour. The solid was filtered off, washed with t-butyl methyl ether (100ml) and dried under vacuum at 40° C. to yield 34.7 g (95%). NMR (300MHz, DMSO-₆): 0.71 (t, 3H), 1.37 (s, 9H), 1.40-1.70 (m, 2H), 3.91-4.01(m, 1H), 5.02 (d, 2H), 5.23 (d, 1H), 6.67 (d, 2H), 7.22 (d, 2H),7.27-7.36 (m, 5H), 7.67-7.74 (m, 1H), 8.32 (d, 1H), 9.37 (brs, 1H).

1. A compound of formula (I):

wherein: Ring A is selected from phenyl or thienyl; X is selected from—CR²R³—, —O—, —NR^(x)— and —S(O)_(a)—; wherein R^(x) is hydrogen orC₁₋₆alkyl, and a is 0-2; Y is selected from —CR⁴R⁵—, —O—, —NR^(z)— and—S(O)_(a)—; wherein R^(z) is hydrogen or C₁₋₆alkyl, and a is 0-2;wherein there is at least one —CR²R³— or —CR⁴R⁵— group; R¹ isindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy andC₁₋₆alkylS(O)_(a) wherein a is 0 to 2; wherein R¹ is independentlyoptionally substituted on carbon by one or more halo, C₁₋₆alkoxy andhydroxy; b is 0-3; wherein the values of R¹ may be the same ordifferent; R² and R³ are independently selected from hydrogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy and C₁₋₆alkanoyloxy; wherein R² and R³ may beindependently optionally substituted on carbon by one or more halo orhydroxy; or R² and R³ together form an oxo group; R⁴ and R⁵ areindependently selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy andC₁₋₆alkanoyloxy; or R⁴ and R⁵ together form an oxo group; R⁶ isindependently selected from halo, nitro, cyano, hydroxy, amino, carboxy,formyl, carbamoyl, carbamoyloxy, mercapto, sulphamoyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkenyloxy, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, C₁₋₆alkanoyl-N-(C₁₋₆alkyl)amino,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl,N-(C₁₋₆alkyl)carbamoyloxy, N,N-(C₁₋₆alkyl)₂carbamoyloxy,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, C₁₋₆alkoxycarbonyl-N-(C₁₋₆alkyl)amino,C₁₋₆alkoxycarbonyloxy, C₁₋₆alkoxycarbonylamino, ureido,N′-(C₁₋₆alkyl)ureido, N-(C₁₋₆alkyl)ureido, N′,N′-(C₁₋₆alkyl)₂ureido,N′-(C₁₋₆alkyl)-N-(C₁₋₆alkyl)ureido,N′,N′-(C₁₋₆alkyl)₂-N-(C₁₋₆alkyl)ureido, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl and phenyl; wherein R⁷ is independentlyoptionally substituted on carbon by one or more halo, C₁₋₆alkoxy,hydroxy, amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkanoylamino,C₁₋₆alkanoyl-N-(C₁₋₆alkyl)amino, phenyl, phenoxy, benzoyl,phenylC₁₋₆alkyl and phenylC₁₋₆alkoxy; c is 0-5; wherein the values of R⁶may be the same or different; R⁷ is independently selected from halo,hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl,mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl,methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl; d is 0-4; whereinthe values of R⁷ may be the same or different; R⁹ is hydrogen,C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁹ may be optionallysubstituted on carbon by one or more substituents selected from R²³; andwherein if said heterocyclyl contains an —NH— group, that nitrogen maybe optionally substituted by a group selected from R²⁴; R¹⁰ is hydrogenor C₁₋₄alkyl; R¹¹ and R¹² are independently selected from hydrogen,C₁₋₄alkyl, carbocyclyl or heterocyclyl; or R¹¹ and R¹² together formC₂₋₆alkylene; wherein R¹¹ and R¹² or R¹¹ and R¹² together may beindependently optionally substituted on carbon by one or moresubstituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— moiety, that nitrogen may be optionally substituted byone or more R²⁶; R¹³ is hydrogen, C₁₋₄alkyl, carbocyclyl orheterocyclyl; wherein R¹³ may be optionally substituted on carbon by oneor more substituents selected from R²⁷; and wherein if said heterocyclylcontains an —NH— moiety, that nitrogen may be optionally substituted byone or more R²⁸; R¹⁴ is hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy, N-(C₁₋₁₀alkyl)amino,N,N-(C₁₋₁₀alkyl)₂amino, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R²⁹—(C₁₋₁₀alkylene)_(f)-,heterocyclyl-(C₁₋₁₀alkylene)_(g)-R³⁰—(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, phosphono, —P(O)(OR³¹)(OR³²), —P(O)(OH)(OR³¹),—P(O)(OH)(R³¹) or —P(O)(OR³¹)(R³²) wherein R³¹ and R³² are independentlyselected from C₁₋₆alkyl; wherein R¹⁴ may be optionally substituted oncarbon by one or more substituents selected from R³³; and wherein ifsaid heterocyclyl contains an —NH— group, that nitrogen may beoptionally substituted by a group selected from R³⁴; or R¹⁴ is a groupof formula (IA):

wherein: Z is —N(R³⁵)—, —N(R³⁵)C(O)—, —O—, and —S(O)_(a)—; wherein a is0-2 and R³⁵ is hydrogen or C₁₋₄alkyl; R¹⁵ is hydrogen or C₁₋₄alkyl; R¹⁶and R¹⁷ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR³⁶)(OR³⁷), —P(O)(OH)(OR³⁶), —P(O)(OH)(R³⁶)or —P(O)(OR³⁶)(R³⁷), wherein R³⁶ and R³⁷ are independently selected fromC₁₋₆alkyl; wherein R¹⁶ and R¹⁷ may be independently optionallysubstituted on carbon by one or more substituents selected from R³⁸; andwherein if said heterocyclyl contains an —NH— group, that nitrogen maybe optionally substituted by a group selected from R³⁹; R¹⁸ is selectedfrom hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino, C₁₋₁₀alkanoylamino,N-(C₁₋₁₀alkyl)carbamoyl, C₁₋₁₀alkoxycarbonyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl, carbocyclylC₁₋₁₀alkyl, heterocyclyl,heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁴⁰—(C₁₋₁₀alkylene)_(f)- orheterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁴¹—(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, phosphono, —P(O)(OR⁴²)(OR⁴³), —P(O)(OH)(OR⁴²),—P(O)(OH)(R⁴²) or —P(O)(OR⁴²)(R⁴³) wherein R⁴² and R⁴³ are independentlyselected from C₁₋₆alkyl; wherein R¹⁸ may be optionally substituted oncarbon by one or more substituents selected from R⁴⁴; and wherein ifsaid heterocyclyl contains an —NH— group, that nitrogen may beoptionally substituted by a group selected from R⁴⁵; or R¹⁸ is a groupof formula (IB):

wherein: R¹⁹ is selected from hydrogen or C₁₋₄alkyl; R²⁰ is selectedfrom hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl,carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono,—P(O)(OR⁴⁶)(OR⁴⁷), —P(O)(OH)(OR⁴⁶), —P(O)(OH)(R⁴⁶) or —P(O)(OR⁴⁶)(R⁴⁷),wherein R⁴⁶ and R⁴⁷ are independently selected from C₁₋₆alkyl; where R²⁰may be independently optionally substituted on carbon by one or moresubstituents selected from R⁴⁸; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R⁴⁹; R²¹ is selected from halo, nitro, cyano,hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy,C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N-(C₁₋₁₀alkyl)amino, N,N-(C₁₋₁₀alkyl)₂amino, C₁₋₁₀alkanoylamino,N-(C₁₋₁₀alkyl)carbamoyl, N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a)wherein a is 0 to 2, N-(C₁₋₁₀alkyl)sulphamoyl,N,N-(C₁₋₁₀alkyl)₂sulphamoyl, N-(C₁₋₁₀alkyl)sulphamoylamino,N,N-(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁵⁰—(C₁₋₁₀alkylene)_(f)-,heterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁵¹—(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, phosphono, —P(O)(OR⁵²)(OR⁵³), —P(O)(OH)(OR⁵²),—P(O)(OH)(R⁵²) or —P(O)(OR⁵³)(R⁵³) wherein R⁵² and R⁵³ are independentlyselected from C₁₋₆alkyl; wherein R²¹ may be independently optionallysubstituted on carbon by one or more R⁵⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R⁵⁵; p is 1-3; wherein the valuesof R¹⁶ may be the same or different; q is 0-1; r is 0-3; wherein thevalues of R¹⁷ may be the same or different; m is 0-2; wherein the valuesof R¹³ may be the same or different; n is 1-2; wherein the values of R⁹may be the same or different; z is 0-3; wherein the values of R²⁰ may bethe same or different; R²³, R²⁵, R²⁷, R³³, R³⁸, R⁴⁴, R⁴⁸ and R⁵⁴ areindependently selected from halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, C₁₋₁₀alkoxycarbonyl, N-(C₁₋₁₀alkyl)amino,N,N-(C₁₋₁₀alkyl)₂amino, C₁₋₁₀alkanoylamino, N-(C₁₋₁₀alkyl)carbamoyl,N,N-(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N-(C₁₋₁₀alkyl)sulphamoyl, N,N-(C₁₋₁₀alkyl)₂sulphamoyl,N-(C₁₋₁₀alkyl)sulphamoylamino, N,N-(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(e)-R⁵⁶—(C₁₋₁₀alkylene)_(f)-,heterocyclyl-(C₁₋₁₀alkylene)_(g)-R⁵⁷—(C₁₋₁₀alkylene)_(h)-, carboxy,sulpho, sulphino, amidino, phosphono, —P(O)(OR⁵⁸)(OR⁵⁹),—P(O)(OH)(OR⁵⁸), —P(O)(OH)(R⁵⁸) or —P(O)(OR⁵⁹)(R⁵⁹), wherein R⁵⁸ and R⁵⁹are independently selected from C₁₋₆alkyl; wherein R²³, R²⁵, R²⁷, R³³,R³⁸, R⁴⁴, R⁴⁸ and R⁵⁴ may be independently optionally substituted oncarbon by one or more R⁶⁰; and wherein if said heterocyclyl contains an—NH— group, that nitrogen may be optionally substituted by a groupselected from R⁶¹; R²⁴, R²⁶, R²⁸, R³⁴, R³⁹, R⁴⁵, R⁴⁹, R⁵⁵ and R⁶¹ areindependently selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,sulphamoyl, N-(C₁₋₆alkyl)sulphamoyl, N,N-(C ₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkoxycarbonyl, carbamoyl, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, benzyl, phenethyl, benzoyl, phenylsulphonyland phenyl; R²⁹, R³⁰, R⁴⁰, R⁴¹, R⁵⁰, R⁵¹, R⁵⁶ and R⁵⁷ are independentlyselected from —O—, —NR⁶²—, —S(O)_(x)—, —NR⁶²C(O)NR⁶³—, —NR⁶²C(S)NR⁶³—,—OC(O)N═C—, —NR⁶²C(O)— or —C(O)NR⁶²—; wherein R⁶² and R⁶³ areindependently selected from hydrogen or C₁₋₆alkyl, and x is 0-2; R⁶⁰ isselected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro,carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy,methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl andN,N-dimethylsulphamoyl; and e, f, g and h are independently selectedfrom 0-2; or a pharmaceutically acceptable salt, or a prodrug thereof.2. A compound of formula (I) according to claim 1 wherein X is selectedfrom —CH₂—, —CH(OH)—, —C(O)—, —O— —S—, —S(O)— and —S(O)₂—; or apharmaceutically acceptable salt, or a prodrug thereof.
 3. A compound offormula (I) according to claim 1 wherein Y is —CH₂—, —S— or —S(O)—; or apharmaceutically acceptable salt, or a prodrug thereof.
 4. A compound offormula (I) according to any one of claims 1 to 3 wherein R¹ is halo; ora pharmaceutically acceptable salt, or a prodrug thereof.
 5. A compoundof formula (I) according to any one of claims 1 to 3 wherein b is 0-1;or a pharmaceutically acceptable salt, or a prodrug thereof.
 6. Acompound of formula (I) according to any one of claims 1 to 3 wherein R⁶is halo; or a pharmaceutically acceptable salt, or a prodrug thereof. 7.A compound of formula (I) according to any one of claims 1 to 3 whereinc is 0-1; or a pharmaceutically acceptable salt, or a prodrug thereof.8. A compound of formula (I) according to any one of claims 1 to 3wherein d is 0; or a pharmaceutically acceptable salt, or a prodrugthereof.
 9. A compound of formula (I) according to any one of claims 1to 3 wherein R⁹ is hydrogen; or a pharmaceutically acceptable salt, or aprodrug thereof.
 10. A compound of formula (I) according to any one ofclaims 1 to 3 wherein R¹⁰ is hydrogen; or a pharmaceutically acceptablesalt, or a prodrug thereof.
 11. A compound of formula (I) according toany one of claims 1 to 3 wherein R¹¹ and R¹² are independently selectedfrom hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹¹ and R¹² may beindependently optionally substituted on carbon by one or moresubstituents selected from R²⁵; wherein R²⁵ is selected from hydroxy,amino, carbamoyl, C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkoxycarbonylamino,carbocyclyl or carboxy; wherein R²⁵ may be optionally substituted oncarbon by one or more R⁶⁰; wherein R⁶⁰ is hydroxy; or a pharmaceuticallyacceptable salt, or a prodrug thereof.
 12. A compound of formula (I)according to any one of claims 1 to 3 wherein R¹³ is hydrogen; or apharmaceutically acceptable salt, or a prodrug thereof.
 13. A compoundof formula (I) according to any one of claims 1 to 3 wherein R¹⁴ ishydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, carboxy orsulpho; wherein R¹⁴ may be optionally substituted on carbon by one ormore substituents selected from R³³; or R¹⁴ is a group of formula (IA)(as depicted above in claim 1) wherein: R¹⁵ hydrogen; R¹⁶ and R¹⁷ areindependently selected from hydrogen, carboxy, C₁₋₆alkyl andC₁₋₆alkoxycarbonyl; R¹⁸ is selected from hydroxy, C₁₋₁₀alkyl,C₁₋₁₀alkoxy, C₁₋₁₀alkoxycarbonyl, carboxy and sulpho; p is 1; q is 0; ris 0 or 1; m is 0 or 1; n is 1; and R³³ is hydroxy; or apharmaceutically acceptable salt, or a prodrug thereof.
 14. A compoundof formula (I) according to any one of claims 1 to 3 wherein m is 0 or1; or a pharmaceutically acceptable salt, or a prodrug thereof.
 15. Acompound of formula (I) according to any one of claims 1 to 3 wherein nis 1; or a pharmaceutically acceptable salt, or a prodrug thereof.
 16. Acompound of formula (I) (as depicted in claim 1) wherein: Ring A isselected from phenyl or thienyl; X is selected from —CH₂—, —CH(OH)—,—C(O)—, —O— —S—, —S(O)— and —S(O)₂—; Y is —CH₂—, —S— or —S(O)—; R¹ isfluoro; b is 0-1; R⁶ is fluoro; c is 0-1; d is 0; R⁹ hydrogen; R¹⁰hydrogen; One of R¹¹ and R¹² is hydrogen and the other is selected fromhydrogen, methyl, hydroxymethyl, 2-carbamoylethyl,2-(ethoxycarbonyl)ethyl, 2-carboxyethyl, 4-(t-butoxycarbonylamino)butyl,4-aminobutyl, isobutyl, phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl; R¹³is hydrogen; R¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl,t-butoxycarbonyl, carboxy or sulpho; wherein R¹⁴ may be optionallysubstituted on carbon by one or more substituents selected from R³³; orR¹⁴ is a group of formula (IA) (as depicted above) wherein: R¹⁵hydrogen; R¹⁶ and R¹⁷ are independently selected from hydrogen, carboxy,C₁₋₆alkyl and t-butoxycarbonyl; R¹⁸ is selected from hydroxy, methyl,t-butoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy and sulpho; p is 1;q is 0; r is 0 or 1; m is 0 or 1; n is 1; and R³³ is hydroxy; or apharmaceutically acceptable salt, or a prodrug thereof.
 17. A compoundof formula (I) (as depicted in claim 1) selected from:1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-((R)-α-{N-(S)-[1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[(R)-α-(carboxy)benzyl]carbamoylmethoxy}phenyl)azetidin-2-one;1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{N-[N-(carboxymethyl)carbamoylmethyl]carbamoylmethoxy}phenyl)azetidin-2-one;1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-hydroxyethyl)carbamoylmethoxy]phenyl}azetidin-2-one;1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[N-(2-methoxyethyl)carbamoylmethoxy]phenyl}azetidin-2-one;3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-(carboxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;3-(R)-4-(R)-1-(phenyl)-3-[2-(thien-3-yl)-2-hydroxyethylsulphanyl]-4-{4-[N-(cabroxymethyl)carbamoylmethoxy]phenyl}azetidin-2-one;3-(R)-4-(R)-1-(phenyl)-3-[2-(thien-3-yl)-2-hydroxyethylsulphanyl]-4-{4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;3-(R)-4-(R)-1-(phenyl)-3-(4-fluorobenzoylmethylsulphanyl)-4-(4-[N-((R)-α-{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;and3-(R)-4-(R)-1-(phenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethylsulphanyl]-4-{4-[N-((R)-α{N-[(S)-1-(carboxy)-2-(hydroxy)ethyl]carbamoyl}benzyl)carbamoylmethoxy]phenyl}azetidin-2-one;or a pharmaceutically acceptable salt, or a prodrug thereof.
 18. Aprocess for preparing a compound of formula (I) or a pharmaceuticallyacceptable salt, or a prodrug thereof which process (wherein variablegroups are, unless otherwise specified, as defined in claim 1) comprisesof: Process 1) reacting a compound of formula (II):

with a compound of formula (III):

wherein L is a displaceable group; Process 2) reacting an acid offormula (IV):

or an activated derivative thereof; with an amine of formula (V):

Process 3): for compounds of formula (I) wherein R¹⁴ is a group offormula (IA); reacting a compound of formula (VI) wherein R¹⁴ iscarboxy, or an activated derivative thereof, with an amine of formula(VI):

Process 4): for compounds of formula (I) wherein R¹⁴ is a group offormula (IA), Z is —N(R³⁵)C(O)— and q is 1; reacting an acid of formula(VII):

or an activated derivative thereof with an amine of formula (VIII):

Process 5): for compounds of formula (I) wherein R¹⁴ is a group offormula (IA) and R¹⁸ is a group of formula (IB); reacting an acid offormula (I) wherein R¹⁴ is a group of formula (IA) and R¹⁸ is carboxy,or an activated derivative thereof, with an amine of formula (IX)

Process 6): reacting a compound of formula (X):

with a compound of formula (XI):

wherein L is a displaceable group; Process 7): for compounds of formula(I) wherein X is selected from —O—, —NR^(x)— and —S(O)_(a)— wherein a is0; reacting a compound of formula (XII):

wherein L is a displaceable group; with a compound of formula (XIII):

Process 8): for compounds of formula (I) wherein X is selected from —O—,—NR^(x)— and —S(O)_(a)— wherein a is 0; reacting a compound of formula(XIV):

with a compound of formula (XV):

wherein L is a displaceable group; Process 9): for compounds of formula(I) wherein Y is selected from —O—, —NR^(z)— and —S(O)_(a)— wherein a is0; reacting a compound of formula (XVI):

with a compound of formula (XVII):

wherein L is a displaceable group; Process 10): for compounds of formula(I) wherein Y is selected from —O—, —NR^(z)— and —S(O)_(a)— wherein a is0; reacting a compound of formula (XVIII):

wherein L is a displaceable group; with a compound of formula (XIX):

Process 11): for compounds of formula (I) wherein X or Y is —S(O)_(a)—and a is 1 or 2; oxidizing a compound of formula (I) wherein X or Y is—S(O)_(a)— and a is 0 (for compounds of formula (I) wherein and a is 1or 2) or a is 1 (for compounds of formula (I) wherein and a is 2); andthereafter if necessary or desirable: i) removing any protecting groups;ii) forming a pharmaceutically acceptable salt, or a prodrug; or iii)separating two or more enantiomers.
 19. A pharmaceutical compositionwhich comprises a compound of formula (I), or a pharmaceuticallyacceptable salt, or a prodrug thereof, as claimed in any one of claims1-3, in association with a pharmaceutically-acceptable diluent orcarrier.
 20. A method for producing a cholesterol absorption inhibitoryeffect in a warm-blooded animal in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, or a prodrugthereof, as claimed in any one of claims 1-3.
 21. A method of treatinghyperlipidaemic conditions in a warm-blooded animal in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt, or a prodrug thereof, as claimed in any one of claims 1-3.
 22. Acombination of a compound of formula (I), or a pharmaceuticallyacceptable salt, or a prodrug thereof, as claimed in any one of claims1-3, and an HMG Co—A reductase inhibitor, or a pharmaceuticallyacceptable salt, or a prodrug thereof.
 23. A combination according toclaim 22 wherein the HMG Co—A reductase inhibitors is selected fromfluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin,cerivastatin, bervastatin, dalvastatin, pitvastatin, mevastatin androsuvastatin, or a pharmaceutically acceptable salt, or a prodrugthereof.
 24. A pharmaceutical composition which comprises a combinationaccording to claim 22, in association with a pharmaceutically acceptablediluent or carrier.
 25. A method for producing a cholesterol absorptioninhibitory effect in a warm-blooded animal in need of such treatmentwhich comprises administering to said animal an effective amount of acombination according to claim
 22. 26. A method of treating ahyperlipidaemic condition in a warm-blooded animal in need of suchtreatment which comprises administering to said animal an effectiveamount of a combination according to claim
 22. 27. The method of claim20 wherein the warm-blooded animal is a human.
 28. The method of claim21 wherein the warm-blooded animal is a human.
 29. The method of claim25 wherein the warm-blooded animal is a human.
 30. The method of claim26 wherein the warm-blooded animal is a human.
 31. A method forproducing a cholesterol absorption inhibitory effect in a warm-bloodedanimal in need of such treatment, which method comprises administeringto said animal an effective amount of the pharmaceutical compositionaccording to claim
 24. 32. The method of claim 31 wherein thewarm-blooded animal is a human.
 33. A method of treating ahyperlipidaemic condition in a warm-blooded animal in need of suchtreatment, which method comprises administering to said animal aneffective amount of the pharmaceutical composition according to claim24.
 34. The method of claim 33 wherein the warm-blooded animal is ahuman.
 35. A combination of a compound of formula (I), or apharmaceutically acceptable salt, or a prodrug thereof, as claimed inany one of claims 1-3, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, or a prodrug thereof.
 36. Acombination according to claim 35 wherein the PPAR alpha and/or gammaagonist is selected from WY-14643, clofibrate, fenofibrate, bezafibrate,GW 9578, pioglitazone, rosiglitazone, eglitazone, proglitazone, BMS298585, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW0207, L-796449, L-165041, and GW 2433, or a pharmaceutically acceptablesalt, or a prodrug thereof.
 37. A combination according to claim 35wherein the PPAR alpha and/or gamma agonist is fenofibrate, or apharmaceutically acceptable salt, or a prodrug thereof.